Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[C:34](=O)[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]4=O)[CH2:18][CH2:17]3)=[CH:14][S:13][C:12]=2[CH:37]=1.O.[OH-].[Na+]>O1CCCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH:27]=[C:28]5[C:33]([CH:32]=[CH:31][CH:30]=[CH:29]5)=[CH:34]4)[CH2:20][CH2:21]3)=[CH:14][S:13][C:12]=2[CH:37]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2csc3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2c(N3CCN(CCCCn4cc5ccccc5c4)CC3)csc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To a stirred suspension of LiAlH4 (1.50 g, 37.9 mmol) in anhydrous tetrahydrofuran (100 mL) under a nitrogen atmosphere at room temperature was added dropwise a solution of 2-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-1H-isoindole-1,3(2H)-dione (5.95 g, 13.6 mmol) in anhydrous tetrahydrofuran (125 mL) over 20 minutes. After the addition the reaction was stirred at 50° C. for 4 hours and then cooled to room temperature. The reaction was treated sequentially with water (1.5 mL), 15% NaOH (1.5 mL), and water (4.5 mL) and stirred at room temperature for 0.5 hours. The mixture was filtered, the insolubles washed with CHCl3 (2 ×50 mL), and the filtrate concentrated in vacuo. The residue was dissolved in chloroform (200 mL), washed with water (100 mL), dried (K2CO3), and the solvent removed in vacuo. The crude product was chromatographed on silica gel with 10% methanol in dichloromethane as eluent to afford 3.50 g of a tan solid. The solid was recrystallized twice from ethyl acetate to afford 1.48 g (26%) of the title compound as amber crystals, m.p. 118°-120° C.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5])#[N:2].[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([C:3](=[C:9]([C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 67.5 %

Procedure:
To a solution of ethyl 2-cyano-3,3-bis(4-fluorophenyl)-2-propenoate (5.0 g, 16 mmol) in tetrahydrofuran (30 mL) at 0° C. was added a solution of 1 M lithium hydroxide in water (30 ML). Saponification reaction was allowed to proceed at 0° C. for a total of three hours forming a clear homogeneous solution. Crude reaction mixture was made acidic by adding 15 mL of 3 M HCl solution in water and the organic material was extracted twice into diethyl ether. Organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give a pale solid. Recrystallization from ethyl acetate-hexanes mixture (1:9 v/v) yielded 3.08 g of the title compound; m.p.=180°-181° C. Another 1.37 g of the desired product was also isolated from the mother liquor making the total combined yield of the title compound over 97%.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH2:21][CH3:22])/[C:16]([O:18]CC)=[O:17])[CH:11]=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:38])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:31])[CH:24]=1)[CH2:4][CH2:5][CH3:6]>C(O)C.O1CCCC1>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH2:21][CH3:22])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:38])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:31])[CH:24]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2OCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)O)cc2OCCCC)c1
Temperature: 50 °C
Yield: 66.4 %

Procedure:
40 mg (1 mmol) of sodium hydroxide are added to a solution of 483 mg (1 mmol) of ethyl 2-[1-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate in 1 mL of ethanol and 10 mL of tetrahydrofuran. The reaction mixture is heated at 50° C. for 48 hours. The reaction medium is evaporated to dryness, taken up in water and acidified with aqueous 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the oil obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture and then precipitated from heptane. 310 mg (83%) of 2-[1-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]butyric acid are obtained in the form of a white powder with a melting point of 98-100° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[N:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:27]1[CH:32]=[C:31]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1nc(-c2cccc(C#N)c2)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cccc(-c2nc(C(=O)O)sc2-c2cccc(Cl)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At room temperature, 2.2 ml of an aqueous 2M sodium carbonate solution and 30.8 mg (0.027 mmol) of tetrakis(triphenylphosphine)palladium are added to 300 mg (0.890 mmol) of the compound from Example 35A and 209 mg (1.34 mmol) of (3-chlorophenyl)boronic acid in 12 ml of DME, and the mixture is subsequently stirred at 80° C. overnight. The crude product is filtered through a short kieselguhr column and the filtrate is concentrated under reduced pressure. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 132 mg (37% of theory) of the title compound having a purity of 85% are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH3:14])[N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc2ccc(Cl)nn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-one [P. Francavilla and F. Lauria, J. Het. Chem. 8, 415 (1971)] (1, 8.5 g., 50 m.mol.) in dry DMF (12 ml.) was added NaH (50% dispersion in paraffin, 2.64 g., 55 m.mol) and the mixture was stirred for 1 hour at room temperature. After methyl iodide (21.3 g., 150 m.mole) was added, the mixture was stirred for 40 hours at room temperature, diluted with water (200 ml.) and extracted with CHCl3 (4 × 100 ml.). The combined extracts were washed with water (3 × 50 ml.), treated with a small amount of carbon and dried with anhydrous Na2SO4. Evaporation of the solvent under reduced pressure afforded pale yellow residue which was crystallized from chloroform-n-hexane. Yield: 7.23 g. (79%). M.p. 180°-181° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6]/[CH:7]=[CH:8]/[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:5])[CH3:2].[N+:13]([CH3:16])([O-:15])=[O:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH:8]([CH2:16][N+:13]([O-:15])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C/C=C/CC(C)C
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC(CC(C)C)C[N+](=O)[O-]

Procedure:
0.485 mol (75.8 g) of the (2E)-5-methyl-hex-2-ene carboxylic acid ethyl ester produced according to 2.1. were dissolved under a nitrogen atmosphere in THF (abs.). 0.73 mol (39.1 ml) of nitromethane and 0.49 mol (485 ml) of a 1 molar tetrabutylammonium fluoride solution in THF were added, wherein an orange solution arose. The mixture was refluxed for 20 hours. After cooling, the mixture was combined with 280 ml of water and extracted four times with diethyl ether. The organic phase was extracted three times with 10% aqueous potassium hydrogensulfate solution and washed to neutrality with water. The organic phase was dried with magnesium sulfate and evaporated in a rotary evaporator. An orange liquid was obtained. The crude yield amounted to 95.2 g (90% of theoretical).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[OH:61][CH2:62][C:63](=[O:70])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66].[OH-].[Na+]>>[OH:70][C@H:63]([CH2:62][OH:61])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66]
Reactant: CCOC(=O)CC(=O)CO
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: CCOC(=O)C[C@H](O)CO
Temperature: 30 °C
Reaction time: 13 h
Yield: 78.9 %

Procedure:
The recombinant E. coli HB101(pNTS1G) obtained in Example 10 was inoculated in 100 ml of a 2×YT medium sterilized in a 500 ml Sakaguchi flask, and cultured with agitation at 37° C. for 13 hours. Glucose, 7.4 g, 3.2 mg of NADP, and then 4 g of ethyl 4-hydroxyacetoacetate were added to 50 ml of the resultant culture. The culture was stirred at 30° C. while being adjusted at pH 6.5 with a 5 M sodium hydroxide solution to allow for reaction for 18 hours. After the reaction, the reaction solution was subjected to extraction using ethyl acetate, the solvent was removed under decompression, and the concentrate was purified by silica gel column chromatography, to obtain 3.2 g of ethyl (S) -3,4-dihydroxybutyrate. The optical purity of the ethyl (S) -3,4-dihydroxybutyrate was analyzed as follows and found to be 100% e.e. The analysis was performed in the following manner. The sample was reacted with sodium cyanide in ethanol at room temperature to obtain 4-cyano-3-hydroxy ethyl butyrate, which was then changed to a benzoic ester using benzoyl chloride under the presence of pyridine. The optical purity of the benzoic ester was measured by the HPLC method. 1NMR(CDCl3) δ (ppm): 1.30(3H,t), 2.55(2H,m), 3.18(1H,br), 3.55(1H,d), 3.68(1H,d), 4.15(1H,s), 4.20(2H,q); Column: Chiralpak AS (0.46×25 cm) manufactured by Daicel Chemical Industries, Co., Ltd.; Column temperature: 25° C.; Eluent: n-hexane/ethanol of 95/5; Flow rate: 1 ml/min.; Detection: 254 nm; Elution time: 19.6 minutes for (S), 21.3 minutes for (R).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=1[NH2:20].CC(C)([O-])C.[K+]>C1COCC1>[F:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:13]=2[F:12])[C:3]=1[C:4]#[N:5]
Reactant: Nc1ccc(I)cc1F
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(F)cc1Nc1ccc(I)cc1F
Temperature: -65 °C
Reaction time: 21 h
Yield: 173.7 %

Procedure:
In analogy to GP 1, 1 g of 2,4,6-trifluoro-benzonitrile (6.37 mmol; 1 eq.; commercially available) and 2.26 g 2-fluoro-4-iodo-benzenamine (9.55 mmol, 1.5 eq; commercially available) were dissolved in 100 ml of THF. The mixture was cooled to −65° C.; 2.14 g of potassium tert-butoxide (19.1 mmol, 3 eq; commercially available) were added. The mixture was stirred for 35 min at this temperature and another 21 h at RT. The mixture was stirred into 120 ml of ice water and extracted three times with ethyl acetate (100 ml each). The combined organic layers were washed with brine, dryed over sodium sulfate and concentrated to afford 4.137 g of crude product. Purification was achieved by flash chromatography (hexane/ethyl acetate) to afford 646 mg (27.13% yield; 1.73 mmol) of the target compound.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[CH2:4][O:5][C:6]([N:8]1[CH2:14][C@H:13](N)[C:12](=[O:16])[N:11]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:10]2[CH:22]=[C:23](F)[C:24](F)=[CH:25][C:9]1=2)=[O:7].OC(C)(C(NCC(F)(F)C(F)(F)F)=O)C(O)=O.ON1C2C=CC=CC=2N=N1>>[F:29][C:3]([F:2])([F:28])[CH2:4][O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:16])[N:11]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]1=2)=[O:7]
Reactant: N[C@H]1CN(C(=O)OCC(F)(F)F)c2cc(F)c(F)cc2N(CC(F)(F)F)C1=O
Agent: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Product: O=C1CCN(C(=O)OCC(F)(F)F)c2ccccc2N1CC(F)(F)F

Procedure:
In an analogous procedure to that described in Example 1e) the condensation of (S)-3-amino-7,8-difluoro-4-oxo-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid 2,2,2-trifluoro-ethyl ester hydrochloride and (RS)-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid with 1-hydroxy-benzotriazole and N-(3-dimethylaminpropyl)-N′-ethyl-carbodiimide hydrochloride as the condensating agents yielded a 1:1-mixture of the epimeric title compounds as a white foam; MS (m/e): 669 (M+H)+. The two epimers were separated by HPLC on a chiral phase (Chiralpak AD) using a 4:1-mixture of heptane and isopropanol as the eluent yielding the first eluting epimer (−)-(S)-7,8-difluoro-3-[(R or S)-2-hydroxy-2-(2,2,3,3,3-pentafluoro-propylcarbamoyl)-propionylamino]-4-oxo-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid 2,2,2-trifluoro-ethyl ester as a light yellow solid [MS (m/e): 669 (M+H)+] and the second eluting epimer (−)-(S)-7,8-difluoro-3-[(S or R)-2-hydroxy-2-(2,2,3,3,3-pentafluoro-propylcarbamoyl)-propionylamino]-4-oxo-5-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid 2,2,2-trifluoro-ethyl ester as a light yellow foam; MS (m/e): 669 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22]Br)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCCC2=O)CC1
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 113.4 %

Procedure:
To a solution of 2-pyrrolidone (86 mg) in anhydrous dimethylformamide (5 ml) was added sodium hydride (45 mg). the reaction mixture was stirred under nitrogen at 50° C. for 35 minutes. 4-Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (86 mg) in anhydrous dimethylformamide (5 ml) was added. The reaction mixture was stirred at 70° C. overnight. The solvents were removed in vacuo and the crude residue was partitioned between dichloromethane and water, the combined organic extracts were washed with brine, dried (MgSO4) and the solvents removed in vacuo to give a crude product. This was purified using flash chromatography to yield 4-(2-Oxo-pyrrolidin-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (99 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: CCCCCCCCOc1ccc(C(N)=O)c(O)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(C#N)c(O)c1
Yield: 14.4 %

Procedure:
A solution of 2-hydroxy-4-octyloxy-benzamide (5.21 g; 19.7 mmol) and dibutyltinoxide (3.65 g; 14.6 mmol) was refluxed in toluene (60 mL) for 12 days. The reaction mixture was evaporated to dryness on SiO2 and purified by column chromatography (SiO2; EtOAc/PE80-100° C.=1:4) to yield 700 mg (14%) product as yellow crystals. Mp. 69-71° C. MS (Direct; Cl): 248 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:19])([CH3:18])[C:10](=[O:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:19])([CH3:18])[C:10](=[O:17])[C:11]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:22][N:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C(=O)Cn1cncn1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)C(C)(C)Cc1ccc(Cl)cc1)n1cncn1
Yield: 123 %

Procedure:
50 g (0.18 mol) of 1-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-3-butanone are heated under reflux with 23.6 g (0.138 mol) of dimethylformamide dimethylacetal for 8 hours. To isolate the end product, the reaction mixture is concentrated in vacuo. 56.5 g (94.4% of theory) of 1-(4-chlorophenyl)-2,2-dimethyl-5-dimethylamino-4-(1,2,4-triazol-1-yl)-4-penten-3-one of refractive index n20 1.5797 are obtained. ##STR17##
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[C:12]([NH2:26])[N:11]=2)[CH:7]=[CH:6][C:5]=1[Cl:27].[Li+].[OH-]>C1COCC1.O>[NH2:26][C:12]1[N:11]=[C:10]([C:8]2[CH:7]=[CH:6][C:5]([Cl:27])=[C:4]([CH:9]=2)[C:3]([OH:28])=[O:2])[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[C:14]([CH3:25])[N:13]=1
Reactant: COC(=O)c1cc(-c2nc(N)nc(C)c2C#Cc2ccc(N)nc2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2ccc(Cl)c(C(=O)O)c2)c1C#Cc1ccc(N)nc1
Yield: 59.5 %

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.28 g (5.78 mmol) 5-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-chloro-benzoic acid methyl ester using 347 mg (14.4 mmol.) LiOH in 20 mL THF and 1 mL water. The product precipitates and is isolated by filtration. The product is washed with water/acetonitrile (1:1 v/v) yielding 1.30 g (3.44 mmol) desired product, which is used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1Cl
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc([N+](=O)[O-])cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[OH-].[K+].[C:7](#[N:10])[CH:8]=[CH2:9]>O>[CH2:8]([C:7]#[N:10])[CH2:9][O:3][CH2:2][CH2:1][O:4][CH2:9][CH2:8][C:7]#[N:10]
Reactant: OCCO
Reactant: C=CC#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CCCOCCOCCC#N
Reaction time: 8 h

Procedure:
To a 5 liter double walled (for water cooling) glass reactor with a bottom drain and stopcock were charged 930 grams (15 moles) of ethylene glycol and 45.6 grams of 40% aqueous KOH solution. Some 1620 grams (30.0 moles) of acrylonitrile (NC--CH=CH2) were then added dropwise, with stirring, at such a rate that the temperature was kept below 35° C. After the addition was completed the mixture was stirred an additional hour and then allowed to stand overnight. The mixture was then neutralized to a pH of 7 by the addition of 6 molar HCL. After washing was saturated NaCl solution three times, the product was separated from the aqueous layer, dried over CaCl2 and passed through an Al2O3 column to insure that all basic materials had been removed. The yield obtained was 90% of theoretical.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([OH:11])[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].[CH3:22][O:23][C:24]1[C:33]([CH3:34])=[C:32]2[C:27]([C:28](O)=[CH:29][C:30]([C:35]3[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=3)=[N:31]2)=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:28]2[C:27]3[C:32](=[C:33]([CH3:34])[C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[N:31]=[C:30]([C:35]3[S:36][CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[N:39]=3)[CH:29]=2)[CH2:7][C@H:6]1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:4]
Reactant: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Reactant: COC(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC[C@@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a stirred solution of compound 34d (2.18 g, 1.2 eq.), compound 203b (1.58 mg, 1 eq.), and PPh3-PS (polystyrene supported triphenylphosphine) (3.34 g, 2 eq.) in THF (50 mL) was added DIAD (2.1 mL, 2 eq.) under nitrogen. The reaction mixture was stirred at room temperature for 16 hrs. The mixture was filtered, and the filtrated was concentrated in vacuo and purified by chromatography on silica gel (DCM/MeOH) to yield compound 34e as a beige solid in 65% yield. MS (ESI, EI+): m/z=617 (MH+).
Reaction SMILES: C(N(S(F)(F)F)CC)C.[CH3:10][O:11][C:12](=[O:28])[CH:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:14]O.C(Br)(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:10][O:11][C:12]([C:13]1[N:16]=[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[O:27][CH:14]=1)=[O:28]
Reactant: COC(=O)C(CO)NC(=O)Cc1ccc(OC)cc1
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(Cc2ccc(OC)cc2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
DAST (diethylaminosulfur trifluoride) was added to a cold (−78° C.) solution of 3-hydroxy-2-[2-(4-methoxy-phenyl)-acetylamino]-propanoic acid methyl ester (400 mg, 1.5 mmol) in dichloromethane (8 mL). After stirring for 1 h at −78° C., CCl3Br (149 μL, 1.5 mmol) and DBU (226 μL, 1.5 mmol) were added and the reaction was allowed to warm to 25° C. and stirred at this temperature for 12 h. The reaction was poured into saturated aqueous NaHCO3 and the biphasic mixture was extracted with DCM. The combined organic extracts were dried with MgSO4 and purified by column chromatography (hexanes:ethyl acetate from 25 to 100%). 2-(4-Methoxy-benzyl)-oxazole-4-carboxylic acid methyl ester was isolated as a white solid (80 mg, 21%). ESI-MS m/z calc. 247.5, found 248.2 (M+1)+. Retention time of 2.64 minutes. 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 3.92 (s, 3H), 4.12 (s, 2H), 6.87 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H).