Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>C(#N)C>[CH2:28]([N:30]([CH2:12][CH:8]1[O:7][C:6]2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=[C:2]([F:1])[C:11]=2[O:10][CH2:9]1)[CH2:31][CH3:32])[CH3:29]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCN(CC)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-ethylethanamine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.2), 87 (6), 86 (bp), 58 (5), 56 (3).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([OH:28])[C:17]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:21])[CH:18]([CH3:20])[CH3:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:28][CH:16]([C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[Cl:8])[C:17]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([OH:21])[CH:18]([CH3:19])[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(C)C(O)(c1cccnc1)C(O)c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(c1ccc(Cl)cc1Cl)C(O)(c1cccnc1)C(C)C
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
38.2 ml (0.4 mol) of acetic anhydride were added dropwise to a solution of 76 g (0.23 mol) of 1-(2,4-dichlorophenyl)-2-(3-pyridyl)-3-methylbutane-1,2-diol, 197.7 ml (1.318 mol) of triethylamine and about 0.5 g (4 mmol) of 4-N,N-dimethylaminopyridine in 1 1 of methylene chloride while heating at 35° C. After cooling to room temperature, the mixture was stirred for a further 30 minutes and then poured into 500 ml of a saturated sodium bicarbonate solution. The organic phase was separated off and was worked up in a conventional manner to obtain the product. The oily crude product was crystallized by stirring with ethyl acetate. Yield: 56%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH3:9][NH:10][CH3:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:10]([CH3:11])[CH3:9])[S:5][CH:6]=1
Reactant: CNC
Reactant: O=Cc1cc(Br)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)Cc1cc(Br)cs1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To a mixture of 4-bromothiophene-2-carbaldehyde (1.91 g, 10 mmol) and dimethylamine (2 M in THF, 7.5 mL, 15 mmol) in DCE (30 mL) was added NaBH(OAc)3 (2.65 g, 12.5 mmol), followed by AcOH (0.2 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction was quenched with sat. NaHCO3 (20 mL) and brine, and was then extracted with EtOAc (100 mL+30 mL). The solvents were removed in vacuo to afford the crude title compound as a light yellow liquid (1.70 g, 77%). 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 6.84 (s, 1H), 3.60 (s, 2H), 2.29 (s, 6H); MS ESI 219.7 [M+H]+, calcd for [C7H10BrNS+H]+ 220.0.
Reaction SMILES: [CH:1]([C:4]1[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:9](O)=[O:10])[NH:7][N:8]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C[N:22](C)C=O>ClCCl>[CH:1]([C:4]1[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:9]([NH2:22])=[O:10])[NH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)c1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid (Farmaco, 46, 11, 1991, 1337-1350) (6 g, 0.03 mol) in N,N-dimethylformamide (69 μL) and dichloromethane (67 mL) was cooled to −5° C. in ice/acetone. Oxalyl chloride (11.48 g, 0.09 mol) was added over 30 minutes and the reaction mixture stirred for 1 hour, the reaction mixture was then allowed to return to room temperature for 2 hours. The reaction mixture was concentrated in vacuo and remaining solvent azeotroped with dichloromethane. The resulting solid was suspended in tetrahydrofuran (70 mL), cooled to 0° C. and 0.880 ammonia (25 mL) added. The reaction mixture was stirred for 30 minutes and then concentrated in vacuo. The resulting solid was suspended in water, filtered and dried at 70° C. under vacuum to yield the product.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60]2[C:65]([CH:66]3[CH2:68][CH2:67]3)=[C:64](Cl)[N:63]=[CH:62][N:61]=2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].[C:70](=[NH:83])([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.C1(C)C=CC=CC=1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60]2[C:65]([CH:66]3[CH2:68][CH2:67]3)=[C:64]([N:83]=[C:70]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)[N:63]=[CH:62][N:61]=2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2C2CC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(N=C(c3ccccc3)c3ccccc3)c2C2CC2)CC1
Temperature: 95 °C
Yield: 89.3 %

Procedure:
A round bottom flask was charged with Pd(OAc)2 (84 mg, 0.37 mmol) and rac-BINAP (234 mg, 0.37 mmol) and purged with N2. To the flask was added 4-(5-cyclopropyl-6-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.27 g, 3.75 mmol), benzophenone imine (815 mg, 4.50 mmol), NaOBut (793 mg, 8.25 mmol) and toluene (24 mL). The mixture was heated to 95° C. for 1 hour. After cooling to room temperature, the reaction was diluted with EtOAc, filtered through Celite, and concentrated. The crude product was purified by column chromatography (hexanes:EtOAc, 2:1) to give 4-[6-(Benzhydrylidene-amino)-5-cyclopropyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.62 g, 89%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.41 (m, 10H), 3.40 (m, 4H), 3.32 (m, 4H), 1.46 (s, 9H), 0.93 (m, 1H), 0.86 (m, 2H), 0.59 (m, 2H). LCMS (APCI+) m/z 484 [M+H]+; Rt=3.94 min.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][CH2:16][N:17]([C:19](=[O:25])[CH2:20][O:21]C(=O)C)[CH:18]=3)=[C:9]([F:26])[CH:8]=2)[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[OH:21][CH2:20][C:19]([N:17]1[CH:18]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:26])[CH2:14][CH2:15][CH2:16]1)=[O:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CN(C(=O)COC(C)=O)CCC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CN(C(=O)CO)CCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-N-[[2-Oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,4-dihydro-2H-pyridin-5-yl]phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 72, Step 6, 238 mg) and anhydrous potassium carbonate (151 mg) in methanol (27 mL) is stirred under N2 at ambient temperature for 2 hrs and is then neutralized with hydrochloric acid (1 M) and concentrated under reduced pressure. The residue is then diluted with methylene chloride (100 mL) and saline (50 mL) and the resultant insoluble product is removed by filtration and dried under reduced pressure. The layers in the filtrate are separated and the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give additional quantities of the title compound, mp 171-173° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5](O)=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:12]=[C:13]([CH3:18])[CH:14]=[CH:15][C:16]=1[NH2:17]>>[CH3:18][C:13]1[CH:14]=[CH:15][C:16]2[NH:17][C:5]([CH:4]3[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]3)=[N:10][C:11]=2[CH:12]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(O)C1CCNCC1
Product: Cc1ccc2[nH]c(C3CCNCC3)nc2c1

Procedure:
The title compound was prepared from isonipecotic acid and 3,4 diamino toluene using the method described in Description 14. MH+ 216.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:7]=1.[NH2:18][NH2:19]>O1CCOCC1>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:9]#[C:8][C:5]1[N:4]=[N:3][C:2]([NH:18][NH2:19])=[CH:7][CH:6]=1
Reactant: Fc1ccc(C#Cc2ccc(Cl)nn2)c(F)c1
Reactant: NN
Solvent: C1COCCO1
Product: NNc1ccc(C#Cc2ccc(F)cc2F)nn1
Temperature: 80 °C
Yield: 95.5 %

Procedure:
A flask was charged with 3-chloro-6-((2,4-difluorophenyl)ethynyl)pyridazine (1.60 g, 6.38 mmol) and 1,4-dioxane (15 mL) to give a tan solution. Anhydrous hydrazine (2.00 mL, 63.8 mmol) was added and the mixture was heated at about 80° C. for about 1 h. The mixture was cooled to ambient temperature and was concentrated in vacuo to about half the original volume. Water (20 mL) was added, followed by sonication, and filtration. The solids were collected and dried in a vacuum oven overnight at about 50° C. to afford the title compound (1.50 g, 95%): LC/MS (Table 1, Method b) Rt=1.72 min; MS m/z: 247.1 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][OH:14]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][OH:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCO
Product: O=[N+]([O-])c1ccc(NCCO)cc1

Procedure:
The title compound was prepared from 1-fluoro-4-nitrobenzene and 2-aminoethanol following the procedure described above. MS (ES+): m/z=183.0; 1H NMR (CDCl3, 500 MHz): δ 3.41 (t, 2H), 3.92 (t, 2H), 6.59 (d, 2H), 8.11 (d, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>O1CCCC1>[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)Cc1n[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 25 °C
Yield: 78 %

Procedure:
Ethyl 2-(1H-indazol-3-yl)acetate (9.78 g, 47.9 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Cesium carbonate (46.81 g, 143.7 mmol) was added, and stirred at room temperature for half an hour. Then p-nitro benzyl bromide (10.36 g, 47.96 mmol) was added, reacted for 16 hours, and then the solid was filtered. The filtrate was concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a yellow solid 12.68 g, at a yield of 78.1%.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:21]=[CH:22][N:23]=2)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:2]1[C:3]2[N:4]([N:21]=[CH:22][N:23]=2)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c3ncnn23)CC1
Reactant: OB(O)c1cccs1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)c3ncnn23)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(8-bromo-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)piperazine-1-carboxylate (0.6 g, 1.57 mmol), thiophene-2-boronic acid (0.35 g, 2.74 mmol), tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.21 mmol), Cs2CO3 (2 g, 6.36 mmol), 1,4-dioxane (20 mL) and water (5 mL). After the air was purged by bubbling N2 into the solution, the resulting mixture was stirred at 100° C. under N2 overnight. Work-up: the reaction mixture was diluted with water and extracted with CH2Cl2 (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 0.5 g (82%) of the product as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[CH2:9]([N:11]([CH2:32][CH3:33])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2C=C(C3C=CSC=3)[NH:24][N:23]=2)=[CH:17][CH:16]=1)[CH3:10]>C(Cl)Cl.CO>[CH2:32]([N:11]([CH2:9][CH3:10])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[CH:2]=[C:1]([C:4]3[S:5][CH:6]=[CH:7][CH:8]=3)[NH:24][N:23]=2)=[CH:17][CH:16]=1)[CH3:33]
Reactant: CC(=O)c1cccs1
Reactant: CCN(CC)CCOc1ccc(Nc2cc(-c3ccsc3)[nH]n2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2cc(-c3cccs3)[nH]n2)cc1

Procedure:
The title compound is prepared as described in Example 33 but using 2-acetylthiophene and diethyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-amine (Example 37). Title compound: ES-MS: 357.1 [M+H]+; single peak at tR=2.98 min (System 2); Rf=0.11 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5](Br)=[C:4]([F:12])[C:3]=1[F:13].C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)CCC>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.C1(C)C=CC=CC=1>[F:13][C:3]1[C:4]([F:12])=[C:5]([C:21]2[S:20][CH:19]=[CH:23][CH:22]=2)[C:6]2[C:7]([C:2]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[N:8][S:9][N:10]=2
Reactant: Fc1c(F)c(Br)c2nsnc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Fc1c(F)c(-c2cccs2)c2nsnc2c1-c1cccs1
Temperature: 105 °C
Yield: 82 %

Procedure:
4,7-Dibromo-5,6-difluoro-benzo[1,2,5]thiadiazole (0.29 g, 1 mmol), tributyl-thiophen-2-yl-stannane (0.86 g, 2.3 mmol), and Pd(PPh3)4 (20 mg) were combined into a 50-mL Schlenk flask. The system was vacuumed and backfilled with argon for three cycles before 20 mL anhydrous toluene was added. The mixture was heated at 105° C. for 4 days. After the reaction was cooled down, the solvent was removed by rotary evaporation. The product was further purified by silica gel column with toluene/hexane (v/v, 1/2) as the eluent and recrystallization from a hexane/iso-propoanol mixture. The final product (0.276 g, 93.0% yield) was obtained as red needle crystals after being dried in vacuo. 1H NMR (CDCl3, 500 MHz): δ 8.33 (d×d, 2H, J=4.0 Hz×1.0 Hz), δ 7.66 (d×d, 2H, J=5.5 Hz×1.0 Hz), δ 7.30 (d×d, 2H, J=5.5 Hz×4.0 Hz)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25]([NH2:26])=[CH:24][C:23](Cl)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25]([NH2:26])=[CH:24][C:23]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCNCC1
Reactant: CSc1nn2c(N)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N)cc(N3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 59.7 %

Procedure:
0.1 g (1 mmol) of 1-methyl-piperazine was added to a solution of 0.14 g (0.4 mmol) of 3-benzenesulphonyl-5-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine in 5 ml of DMF and stirred at 90° for 1 hr. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was extracted three times with 50 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel CH2Cl2/MeOH 9:1) and crystallization from EtOH yielded 0.1 g (59%) of 3-benzenesulphonyl-5-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:22][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: Nc1ccccc1
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Nc3ccccc3)c2nc1OC
Reaction time: 40 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and aniline 80 μL (0.84 mmol). Reaction was continued for 40 hours, and the crude product was eluted through a flash column (3:2 hexanes:ethyl acetate), 180 mg (62%), mp 238-240° C.; 1H NMR (CDCl3): δ 8.34 (s, 1H), 7.81 (d, 2H, J=8.8 Hz), 7.69 (s, 1H), 7.35 (t, 2H, J=7.6, 8.5 Hz), 7.11 (t, 1H, J=6.3, J=7.3 Hz), 4.17 (s, 3H), 4.02 (s, 3H), 2.58 (s, 3H); (APCI): m/z 369 (M+H). Anal. Calcd. for C18H16N4O5: C, 58.69; H, 4.38; N, 15.21. Found: C, 58.62; H, 4.52; N, 15.06.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[CH3:59][NH:60][O:61][CH3:62]>C(Cl)Cl>[CH3:62][O:61][N:60]([CH3:59])[C:15]([CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)=[O:17]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a cold (0° C.) solution of 3-[(tert-butoxycarbonyl)amino]-cyclohexanecarboxylic acid (5.00 g, 20.6 mmol) in CH2Cl2 (50 mL) including triethylamine (3.1 mL, 22.2 mmol) were added benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexa-fluorophosphate (10.7 g, 20.6 mmol), N,O-dimethylhydroxyamine hydrochloride (2.21 g, 20.6 mmol) and Et3N (3.2 mL, 23.0 mmol) successively. The resulting mixture was allowed to warm to room temperature, and the stirring was continued for 18 hrs. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl, saturated aqueous NaHCO3 solution, and brine, successively. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1:1) to give tert-butyl 3-{[methoxy(methyl)amino]carbonyl}cyclohexylcarbamate as a colorless oil (5.39 g, yield; 92%).
Reaction SMILES: C([Li])CCC.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].CN(C)CCN(C)C.I[CH2:25][CH2:26][O:27][CH2:28][CH2:29]I>C1COCC1>[O:27]1[CH2:28][CH2:29][C:8]2([C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:6][C:7]2=[O:15])[CH2:25][CH2:26]1
Reactant: ICCOCCI
Reactant: O=C1Cc2ccccc2N1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12CCOCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (2.5 M in hexanes, 3.76 mL, 9.39 mmol) was added to a solution of oxindole (500 mg, 3.76 mmol) at −78° C. in THF (40 mL). After complete addition, N,N,N′,N′-tetramethylethane-1,2-diamine (1.48 mL, 9.76 mmol) was added, maintaining the internal temperature <−70° C. After 1 h at −78° C., 2-iodoethyl ether (4.90 g, 15.0 mmol) was added and the reaction warmed to ambient temperature. After 48 h the reaction was quenched with H2O (5 mL) and the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous solution was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 97:3, gave the title compound. MS: m/z=204 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][P:9]([CH2:14][CH:15]([CH2:25][OH:26])[CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:13])[O:10][CH2:11][CH3:12])[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:19]([O:18][P:17]([CH2:16][CH:15]([CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14][P:9](=[O:13])([O:10][CH2:11][CH3:12])[O:8][CH2:6][CH3:7])(=[O:24])[O:21][CH2:22][CH3:23])[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOP(=O)(CC(CO)CP(=O)(OCC)OCC)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CC(COS(C)(=O)=O)CP(=O)(OCC)OCC)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Methanesulfonylchloride (2.2 ml, 28.6 mmol) was added dropwise at 0° C. to a solution of 2-hydroxymethyl-1,3-propylene-bisphosphonic acid tetraethylester (9.0 g, 26.0 mmol) and triethylamine (4.0 ml, 28.6 mmol, 1.1 eq.) in anhydrous dichloromethane (90 ml). The reaction mixture was stirred for 30 min at 0° C. and for 2 h at room temperature. After concentrating in vacuo deionized water (100 ml) was added and the mixture was extracted with ethylacetate (3×100 ml). The combined organic phases were dried with anhydrous sodium sulphate. After removal of the solvent under reduced pressure the obtained crude product was purified by column chromatography (eluent: ethylacetate/methanol 9:1). 9.37 g (85% yield) of the product was obtained as a colorless oil.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:15][CH2:16][CH2:17]CCC>>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[CH2:17][CH:16]=[CH2:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCCCC
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Product: C=CC[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
In an argon atmosphere, 8.39 g (36.0 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 17 mL of hexane and after adding a (prop-2-en-1-yl)magnesium bromide diethyl ether solution (0.99 mol/L, 38.0 mL, 37.6 mmol), the resulting solution was stirred at room temperature for 18 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 88° C./4.4×102 Pa) to obtain 1,3-di-tert-butyl-2-(prop-2-en-1-yl)-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)CH2CHCH2) as a yellow liquid (yielded amount: 7.33 g, yield: 85%).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[OH-].[Na+].C(Cl)(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4.3 Parts of sarcosine and 4.1 parts of sodium hydroxide are dissolved in 100 parts of water. To the resulting solution, 35 parts of chloroform containing 10 parts of p-chlorobenzenesulfonyl chloride is added, and the resulting mixture is stirred at 60° C for about 2 hours. After the reaction, the aqueous layer is separated and then acidified with hydrochloric acid to precipitate crystals. The crystals are collected by filtration and recrystallized from a mixed solvent comprising acetone and water to obtain 4.6 parts of N-p-chlorobenzenesulfonyl-sarcosine, m.p. 180.5°-182° C.