Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5]C(=O)NC1(CCCO)CCC(OC2C=C3C(=CC=2Cl)C(OCC2C=CC=CC=2)=NC=C3)CC1)(C)(C)C.[C:39]([O:43][C:44](=[O:77])[NH:45][C:46]1([CH2:74][CH:75]=[CH2:76])[CH2:53][CH2:52][CH2:51][CH:50]([O:54][C:55]2[CH:56]=[C:57]3[C:62](=[CH:63][C:64]=2[Cl:65])[C:61]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[N:60][CH:59]=[CH:58]3)[CH2:49][CH2:48][CH2:47]1)([CH3:42])([CH3:41])[CH3:40].B1C2CCCC1CCC2>>[C:39]([O:43][C:44](=[O:77])[NH:45][C:46]1([CH2:74][CH2:75][CH2:76][OH:5])[CH2:53][CH2:52][CH2:51][CH:50]([O:54][C:55]2[CH:56]=[C:57]3[C:62](=[CH:63][C:64]=2[Cl:65])[C:61]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[N:60][CH:59]=[CH:58]3)[CH2:49][CH2:48][CH2:47]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)NC1(CCCO)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Reactant: C=CCC1(NC(=O)OC(C)(C)C)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Agent: B1C2CCCC1CCC2
Product: CC(C)(C)OC(=O)NC1(CCCO)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1

Procedure:
1.14 g of [5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-hydroxy-propyl)-cyclooctyl]-carbamic acid tert-butyl ester (59) were synthesized using the procedure described for the synthesis of [4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-hydroxy-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (53) starting from 1.17 g (2.12 mmol) of [1-allyl-5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclooctyl]-carbamic acid tert-butyl ester (58) and 12.7 mL (6.37 mmol) of 9-BBN (0.5M solution in THF). Rt=1.71 min (Method I). Detected mass: 569.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.C([Li])CCC.[C:21]([O:24]CC)(=[O:23])C>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([C:21]([OH:24])=[O:23])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Cc1ccccc1-2
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
A solution of 2-methoxyfluorene (2.7 g, 13.8 mmol) in 50 mL of THF at -78° C. was charged with n-butyl lithium (0.93 g, 14.5 mmol). The reaction mixture was stirred for 15 min then CO, gaseous (5 g, 113.6 mmol) was introduced via cannula over a period of 15 min at -78° C. The reaction mixture was warmed up to room temperature and stirred for additional 2 hr until a colorless solution was obtained. The reaction mixture was diluted with 100 mL of water and 100 mL of ethyl acetate. The layers were separated, the aqueous phase was washed with ethyl acetate (5×25 mL) and acidified to pH 1 with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried to afford 2.2 g (66.7%) of 2-methoxy-9-fluorenecarboxylic acid as colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10][C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C1CNCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl 4-benzyl-3-oxopiperazine-1-carboxylate (4.7 g, 14.5 mmol) and 10% Pd/C (0.47 g) in ethanol (150 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature overnight. The product mixture was filtered through a pad of Celite, and concentrated under vacuum to provide 1-benzylpiperazin-2-one.
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.[H-].[Na+].[CH3:27]I.O>CN(C)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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:27])[CH:20]=[CH:19]2
Reactant: CI
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C)c3)c2cc1OC
Reaction time: 0.5 h
Yield: 62 %

Procedure:
6,7-Dimethoxy-4-[(1H-5-indolyl)oxy]quinoline (50 mg) was dissolved in N,N-dimethylformamide (1 ml), and 60% sodium hydride (7 mg) was added, followed by stirring for 30 min under ice cooling. Methyl iodide (0.0107 ml) was added to the reaction solution, and the mixture was stirred under ice cooling for additional one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (32 mg, yield 62%).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C1(N=C=NC2CCCCC2)CCCCC1.[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46]([CH2:48][C:49](O)=[O:50])=[O:47]>C1C=CC=CC=1>[S:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46]([CH2:48][C:49]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:50])=[O:47]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CS(=O)c1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)CS(=O)c3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
154 mg of t-butyl 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate and 83 mg of dicyclohexylcarbodiimide were dissolved in 5 ml of benzene, and 76 mg of 2-thienylsulfinylacetic acid ([α]D22° :+11.0°, C=1.00, ethanol) was added to the solution. This liquid reaction mixture was agitated at 25° C. for 2 hours. The mixture was filtered, made adsorbed on 2 g of silica gel and subjected to chromatography using benzene-ethyl acetate (50:50) on 20 g of silica gel to obtain 145 mg of t-butyl 7-(2-thienylsulfinylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate. The so obtained ester was dissolved in 1 ml of trifluoroacetic acid, and the solution was agitated at 25° C. for 5 minutes. Then, the solution was added dropwise to 70 ml of ether. The resulting precipitate was collected and dissolved in 5% aqueous sodium bicarbonate solution to form 100 ml of a solution. Then, the solution was extracted with ethyl acetate, and the pH of the aqueous layer was adjusted to 2.0 and the aqueous layer was further extracted with ethyl acetate. The organic layer was dried and concentrated until the volume was reduced to 5 ml. The resulting residue was mixed with a 30% solution of sodium 2-ethylhexanoate in propanol, and ether was added to the mixture. The precipitated salt was collected, recrystallized from methanolether and dried under reduced pressure to obtain 51 mg of sodium 7-(2-thienylsulfinylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate of the R form optically active in the sulfoxide. The NMR spectrum was found to be in agreement with that of the intended product. The bacterium-inhibiting activity of the so obtained compound was much superior to that of the product derived in the same manner by using 2-thienylsulfinylacetic acid having [α]D22° of -9.2° as the starting compound.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:26]#[N:27])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:28])=O.CS(C)=O.[Cl-].[Na+]>O>[O:28]=[C:6]1[CH2:5][CH2:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:13][CH:12]=2)([C:26]#[N:27])[CH2:8][CH2:7]1
Reactant: COC(=O)C1CC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCC(=O)CC1
Temperature: 144 °C
Reaction time: 5 h
Yield: 39.6 %

Procedure:
To a solution of 5-cyano-2-oxo-5-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarboxylic acid methyl ester (6.6 g, 17 mmol) and dimethylsulfoxide (128 mL) was added water (8.0 mL) and sodium chloride (6.4 g, 109 mmol). The reaction mixture was heated to 142-146° C. After 5 hr, the mixture was concentrated and the residue was dissolved in DCM (120 mL), washed with water (100 mL), and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (70 g silica gel, eluant:gradient of DCM/MeOH 95/5 to 90/10) providing 4-oxo-1-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarbonitrile as a crystallizing oil (2.2 g, 45.5%). After crystallization in ether, 0.2 g of analytical sample were obtained. 1H NMR (400 MHz, CDCl3) δ7.32 (d, 2H), 6.88 (d, 2H), 4.1 (t, 2H), 2.95-2.8 (m, 2H), 2.65-2.38 (m, 10H), 2.3-2.15 (m, 2H), 2.0-1.9 (m, 2H), 1.8-1.7 (m, 4H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH2:15])[N:14]=[C:10]2[CH:9]=[C:8]([C:16]2[CH:17]=[N:18][C:19]([N:22]([CH3:24])[CH3:23])=[N:20][CH:21]=2)[CH:7]=1)=O)C.C(OC(C1[N:35]2[N:36]=C(N)N=C2C=C(Br)C=1)=O)C.CN(C)C1N=CC(B(O)O)=CN=1>>[NH2:15][C:13]1[N:14]=[C:10]2[CH:9]=[C:8]([C:16]3[CH:21]=[N:20][C:19]([N:22]([CH3:24])[CH3:23])=[N:18][CH:17]=3)[CH:7]=[C:6]([C:4]([NH:35][NH2:36])=[O:3])[N:11]2[N:12]=1
Reactant: CCOC(=O)c1cc(Br)cc2nc(N)nn12
Reactant: CCOC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(N)nn12
Agent: CN(C)c1ncc(B(O)O)cn1
Product: CN(C)c1ncc(-c2cc(C(=O)NN)n3nc(N)nc3c2)cn1

Procedure:
2-Amino-7-(2-dimethylamino-pyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester, was prepared analogously to Example 28, Step 3, except 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (10.0 g, 35.1 mmol) was used as the starting material (which may be prepared as described in Example 6) and 2-dimethylamino-pyrimidin-5-boronic acid was used in place of 3-pyridyl-boronic acid to give 2-amino-7-(2-dimethylamino-pyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid hydrazide. MS (APCI+): m/z 328.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].O>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(NC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of benzyl [(trans-4-{[(3-chloropyrazin-2-yl)methyl]carbamoyl}cyclohexyl)methyl]carbamate (0.100 g, 0.220 mmol) in EtOAc (0.9 mL) and DMF (0.068 mL) at 0° C. was added slowly POCl3 (0.082 mL, 0.88 mmol). After stirring at rt for an hour, the mixture was cooled to 0° C. and solid NaHCO3 was added. After a further 10 min at 0° C. and 20 min at rt, the mixture was re-cooled to 0° C. and water (20 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the extracts washed with water (2×30 mL) and brine (30 mL) and then dried over Na2SO4 and concentrated in vacuo to afford 0.096 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.15-1.19 (m, 2H), 1.76-1.87 (m, 3H), 1.93-2.00 (m, 2H), 2.04-2.08 (m, 2H), 3.07 (m, 1H), 3.15 (t, J=6.4 Hz, 2H), 4.84 (br, 1H), 5.09 (s, 2H), 7.31-7.40 (m, 6H), 7.61 (d, J=4.8 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 399.26 [MH+].
Reaction SMILES: [CH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:11][C:12](=O)OC(C)(C)C)=O.CO/C=[CH:22]/[C:23]([O:25][CH3:26])=[O:24].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:1]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH:12]=[N:11]2
Reactant: CO/C=C/C(=O)OC
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2cccc(OC)c2c1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a solution of tert-butyl N-(2-formyl-3-methoxyphenyl)carbamate (7.8 g, 31 mmol) [described in Adv. Synth. Catal. 2003, 345, 743-765] and methyl trans-3-methoxyacrylate (7.4 mL, 68.4 mmol) dissolved in 150 ml of methanol, was added slowly 100 mL of an aqueous solution of hydrochloric acid 3M. The resulting mixture was stirred under reflux for 3 hours. The reaction mixture was then cooled to room temperature and neutralised by adding Na2CO3. The aqueous solution was extracted with CH2Cl2 (4×150 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum. The crude product was then filtered on silica gel (AcOEt:cyclohexane/1:1) to afford 5.6 g of compound of molecular formula C12H11NO3. Aspect: yellow powder.
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][C:6]1[N:11](C)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8](=[O:18])(=[O:17])[CH:7]=1)C.[H-].[Na+].N#N.Cl.[CH3:25][C:26]([OH:28])=O>C1COCC1>[O:18]=[S:8]1(=[O:17])[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[NH:11][C:6]([C:5]2[C:4](=[O:19])[NH:11][C:6]([CH3:5])=[C:25]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:10]=3)[C:26]=2[OH:28])=[CH:7]1
Reactant: CCOC(=O)CC1=CS(=O)(=O)c2ccccc2N1C
Reactant: CC(=O)O
Agent: Cl
Agent: N#N
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1[nH]c(=O)c(C2=CS(=O)(=O)c3ccccc3N2)c(O)c1-c1ccccc1
Temperature: 80 °C

Procedure:
step 3—To a solution of 76b (91 mg, 0.33 mmol), 4 (89 mg, 0.33 mmol) and THF (3.5 mL) was added in one portion NaH (26 mg, 0.66 mmol) was then added in one portion. After the evolution of N2 subsided the flask was fitted with a reflux condenser, and heated to 80° C. under a N2 atmosphere. The reaction was subsequently monitored by LCMS. When 76b was not longer detectable by hplc the reaction was cooled to RT and glacial HOAc (500 μL) and 1 N HCl (5.0 mL) were added sequentially. The aqueous phase was then extracted with Et2O (3×50 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated. The crude was then purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (25-40% EtOAc) to afford 61 mg (41%) of III-1 as a yellow semi-solid: LCMS RT 2.34 min, [M−H].
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.OC1C(C(OC)=O)=CN=C(C2N=NC=CC=2)N=1.[OH-].[Na+].C(OC1C(C(OCC)=O)=CN=C(N2C=CC=N2)N=1)C1C=CC=CC=1.C(OC1C(C(O)=O)=CN=C(N2C=CC=N2)N=1)C1C=CC=CC=1.[CH3:82][C:83]1[CH:84]=[CH:85][C:86]([S:89]([NH2:92])(=[O:91])=[O:90])=[CH:87][CH:88]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.CN(C1C=CN=CC=1)C>[OH:1][C:2]1[C:7]([C:8]([NH:92][S:89]([C:86]2[CH:87]=[CH:88][C:83]([CH3:82])=[CH:84][CH:85]=2)(=[O:90])=[O:91])=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CCOC(=O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: COC(=O)c1cnc(-c2cccnn2)nc1O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)c2cnc(-c3cccnn3)nc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 13-b, (350 mg, 1.6 mmol, which was prepared from compound 1-e via sodium hydroxide hydrolysis in a similar manner as the conversion of 3-b to 3-c) in thionyl chloride (10 ml) was heated at reflux for 4 h. The mixture was concentrated under vacuum and the residue was co-evaporated with dichloromethane twice. The remaining oil was dissolved in dichloromethane (10 ml). p-toluenesulfonamide (329 mg, 1.93 mmol), triethylamine (486 mg, 4.82 mmol) and DMAP (390 mg, 3.2 mmol) were added to the solution at room temperature. The mixture was subsequently stirred at room temperature overnight. The mixture was then concentrated under vacuum and the residue was diluted with water (10 ml). The solid crashed out and then filtered out of the solution. The solids were then recrystallization in methanol/ethyl acetate to afford compound 13-1 (300 mg, 50%). 1H NMR (DMSO-d6, 300 MHz): δ 12.92 (br, 1H), 9.51 (s, 1H), 8.53 (s, 2H), 8.00 (m, 3H), 7.46 (s, 2H), 2.41 (s, 3H). (M+H)+=372.1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cu](C#N)[C:13]#[N:14]>CN(C=O)C.C(OCC)(=O)C>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([C:13]#[N:14])=[CH:3][C:4]=2[O:8]1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(=O)oc2c1

Procedure:
A mixture of 6-bromo-3H-benzooxazol-2-one (47) (400 mg, 1.87 mmol, 1 eq), copper cyanide (3.3 g, 37 mmol, 20 eq), in DMF (10 ml) was stirred at 175° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered to remove the precipitated solid material, and the organic phase was washed with water, purified by flash chromatography to give 2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (48).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[S:53](=[O:57])(=[O:56])CC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][S:53](=[O:57])(=[O:56])[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCS(=O)(=O)CC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and thiomorpholine 1,1-dioxide and isolated as white solid (13.5 mg, 66%). MS (m/e): 435.4 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[CH3:25][NH:26][CH3:27]>C1COCC1>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([N:26]([CH3:27])[CH3:25])[N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CNC
Reactant: CC(C)(CO)NC(=O)c1nn(-c2cncc(Cl)n2)c2c1C[C@H]1C[C@@H]21
Solvent: C1CCOC1
Product: CN(C)c1cncc(-n2nc(C(=O)NC(C)(C)CO)c3c2[C@@H]2C[C@@H]2C3)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
(1aR,5aR)-2-(6-Chloro-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (25 mg, 0.072 mmol) was added to a 2.0 M THF solution of dimethylamine (0.719 mL, 1.438 mmol). The reaction was heated under microwave irradiation for 30 min at 100° C., then for 60 min at 110° C. The mixture was concentrated and purified by silica gel flash chromatography to provide the title compound (18 mg) as a white solid. LCMS m/z=357.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.21 (td, J=7.8, 4.8 Hz, 1H), 1.41 (s, 3H), 1.42 (s, 3H), 2.22-2.28 (m, 1H), 2.70-2.75 (m, 1H), 2.90 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.6, 6.3 Hz, 1H), 3.18 (s, 6H), 3.70 (s, 2H), 4.87 (bs, 1H), 6.98 (s, 1H), 7.93 (s, 1H), 8.41 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][OH:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:11][CH2:12][C:13]#[C:14][CH2:15]Cl.[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:15][C:14]#[C:13][CH2:12][Cl:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: ClCC#CCCl
Reactant: CCOP(=O)(CO)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOP(=O)(COCC#CCCl)OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of hydroxymethylphosphonic acid diethylester (3.35 g, 20 mmol), 1,4-dichloro-2-butyne (3.8 g, 30 mmol) and tetra-n-butylammonium iodide,(0.75 g, 2 mmol) in anhydrous tetrahydrofuran (100 ml), sodium hydride (0.95 g, 24 mmol, 60% in oil) is added in portions at 0° C. The resulting mixture is stirred overnight at 0° C. Then the reaction mixture is stirred overnight at 20° C., hydrolyzed with a saturated solution of ammonium chloride and extracted with diethylether. The title product is obtained by flash chromatography on silica gel (2.3 g, 30%).
Reaction SMILES: CCO.[N+:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:16]([OH:18])=[O:17])([O-])=O>[Pd].CC(O)=O>[NH2:4][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(C(=O)O)cc1C(=O)O
Reaction time: 16 h
Yield: 75.1 %

Procedure:
Into 20 mL EtOH and 20 mL HOAc was dissolved 2 g (9.48 mmol) 4-nitroisophthalic acid, and the solution was subjected to hydrogenation at atmospheric conditions over 1 g of 5% Pd on carbon. After 16 h, mixture was filtered, and filtrate was evaporated. The residue crystallized from methylene chloride-hexane, giving 1.29 g (75%) crystalline desired intermediate.
Reaction SMILES: C[Mg+].[Br-].[O:4]=[C:5]([CH3:16])[CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[CH2:17](Cl)Cl.CO>C1COCC1.O>[OH:4][C:5]([CH3:17])([CH3:16])[CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: CC(=O)Cc1cccc(C(=O)O)c1
Reactant: ClCCl
Agent: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)Cc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
CH3MgBr (3.0 M in THF, 11.2 mL, 33.7 mmol) was added slowly to a stirring solution of 3-(2-oxopropyl)benzoic acid (2 g, 11.2 mmol) in THF (100 mL) at 0° C. The resulting suspension was allowed to warm to rt then stirred overnight. The reaction mixture was diluted with H2O (50 mL) then quenched with 5 N HCl (pH<3). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 (s), and concentrated to give a yellow oil. Chromatography (9:1, CH2Cl2/MeOH) afforded the title compound (1.36 g, 62%) as a white solid. ES/MS calcd. for C11H14NaO3+ 217.1, found m/z=217.2 (M+Na)+.
Reaction SMILES: [CH:1]1([C@@H:4]([OH:21])[C@H:5](OS(C2C=CC(C)=CC=2)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C@H:4]2[O:21][C@H:5]2[C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@@H]1O[C@@H]1C1CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 2.97 g of methyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-(p-toluenesulfonyloxy)propionate in 50 ml of acetonitrile are added 10.86 ml of water and 3.96 g of potassium carbonate successively at room temperature. Then, the reaction mixture is stirred at 50° C. for 2 days. The reaction mixture is cooled to room temperature, and insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; diethylether) to give methyl (2R,3R)-3-cyclopropyl-2,3-epoxypropionate quantitatively.