Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH:19]=[C:18]([CH2:20][OH:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[N:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].C(OC(N1CCC(N2C=NC(C[O:45][S:46]([CH3:49])(=O)=[O:47])=N2)CC1)=O)(C)(C)C>>[CH3:49][S:46]([O:21][CH2:20][C:18]1[C:17]([C:22]([F:25])([F:24])[F:23])=[N:16][N:15]([CH:12]2[CH2:11][CH2:10][N:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=3)[CH2:14][CH2:13]2)[CH:19]=1)(=[O:47])=[O:45]
Reactant: CCc1cnc(N2CCC(n3cc(CO)c(C(F)(F)F)n3)CC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(COS(C)(=O)=O)n2)CC1
Product: CCc1cnc(N2CCC(n3cc(COS(C)(=O)=O)c(C(F)(F)F)n3)CC2)nc1

Procedure:
The title compound was synthesized using (1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol in a manner similar to that described in Intermediate 1, Step 3.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([C:27]([O:29]C)=[O:28])[CH2:26][CH2:25]4)=[CH:20][C:19]=3[Cl:31])=[CH:14][CH:13]=2)[C:9]([CH3:32])=[N:8][C:7]=1[CH3:33])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]4)=[CH:20][C:19]=3[Cl:31])=[CH:16][CH:17]=2)[C:9]([CH3:32])=[N:8][C:7]=1[CH3:33])(=[O:5])[NH2:4]
Reactant: COC(=O)C1(c2ccc(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(Cl)c2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3Cl)cc2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
Powdered potassium hydroxide (52.1 mg, 0.93 mmol) was added in one portion to methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclopropanecarboxylate (Intermediate 10-1; 135 mg, 0.31 mmol) in tert-butanol (5 mL) at 45° C. The resulting solution was stirred at 45° C. for 30 minutes. 2N HCl (1 mL) was added and the mixture was evaporated to remove the organic solvent. The suspension was collected by filtration, washed with water and dried under vacuum to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclopropanecarboxylic acid (30.0 mg, 22.96%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH:3]1[C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1.FC(F)(F)C([O-])=O>>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccccc2)cs1
Agent: O=C([O-])C(F)(F)F
Product: CN1CCNCC1c1nc(-c2ccccc2)cs1

Procedure:
This compound was synthesized from tert-butyl 4-methyl-3-(4-phenylthiazol-2-yl)piperazine-1-carboxylate as described for example 46 step 4 (50 mg, crude) as a trifluoroacetate salt and it was taken as such for the next step. MS (ESI) m/z: Calculated for C14H17N3S: 259.11. found: 260.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1N.Cl.N([O-])=O.[Na+].[I-:17].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Br:1][C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[I:17]
Reactant: [I-]
Reactant: Nc1ccc2ncsc2c1Br
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Product: Brc1c(I)ccc2ncsc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 2.6 %

Procedure:
To a suspension of 7-bromo-benzothiazol-6-ylamine (7.6 g, 33.3 mmol) in water (60 mL) was added concentrated hydrochloric acid (6 mL, 72 mmol). The mixture was cooled to 0° C. and stirred for 10 min. A cooled (0° C.) solution of sodium nitrite (5.0 g, 73 mmol) in water (10 mL) was added dropwise to the reaction mixture keeping the internal temperature below 5° C. The mixture was stirred for further 10 min. A solution of potassium iodide (12.1 g, 73 mmol) in water (15 mL) was added to the reaction mixture and was stirred vigorously for 10 min, and then water (200 mL) and 20% aqueous sodium thiosulfate solution (100 mL) were added. The solid formed was extracted with ethyl acetate (3×70 mL). The combined organic fractions were washed with water (100 mL), dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by column chromatography (25% ethyl acetate:hexanes) afforded 0.3 g (5%) of the title compound, plus some impure title compound. The impure title compound was recrystallized 2× from 1:4 DCM:hexanes to afford a further 0.71 g (9%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.99 (s, 1H), 7.95 (d, J=8.4, 1H), 7.77 (d, J=8.4 Hz, 1H).
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:34]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[C:35]1([C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCCC=C(c1ccccc1)c1ccccc1
Yield: 75.2 %

Procedure:
The reaction was carried out as in Example 87 using the following reagents: sodium hydride (56% dispersion in oil; 8.6 g), dimethylsulfoxide (100 mL), (4-carboxybutyl)triphenylphosphonium bromide (36.5 g), benzophenone (18.2 g), and tetrahydrofuran (100 mL). The crude product, isolated in the usual manner, was crystallized from hexane to give 16.5 g of 6,6-diphenyl-5-hexenoic acid, mp 111°-112.5° C. Anal. Calculated for C18H18O2 : C, 81.17; H, 6.81. Found: C, 81.39; H, 6.88.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:10])[C:3]=1[C:20]([O:22]C)=O.[CH3:24][O:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][N:31]2[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]2)=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:10])[C:3]=1[C:20](=[O:22])[NH:36][C:34]1[CH:33]=[N:32][N:31]([CH2:30][C:29]2[CH:37]=[CH:38][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH:35]=1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: COc1ccc(Cn2cc(N)cn2)cc1
Product: COc1ccc(Cn2cc(NC(=O)c3c(Br)ccn3NC(=O)[C@H](C)NC(=O)OC(C)(C)C)cn2)cc1
Yield: 60 %

Procedure:
This compound was prepared starting from (S)-methyl 3-bromo-1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (300 mg, 0.77 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-4-amine (469 mg, 2.31 mmol) following the experimental procedure described in Preparation 27a to afford 271 mg (96% purity, 60% yield) of the title compound after purification by flash chromatography (0% to 70% AcOEt/hexanes).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([N:7]1[CH2:19][C:18]2[S:17][C:16]3[N:15]=[CH:14][N:13]=[C:12]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=4)[C:11]=3[C:10]=2[CH2:9][CH2:8]1)=[O:6].[CH3:29][NH:30][CH3:31].CO.ClCCl>ClCCl>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:12]2[C:11]3[C:10]4[CH2:9][CH2:8][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:30]([CH3:31])[CH3:29])[CH2:19][C:18]=4[S:17][C:16]=3[N:15]=[CH:14][N:13]=2)[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CNC
Reactant: O=C(C=CCBr)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Solvent: CO
Solvent: ClCCl
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
To an ice-bathed cooled solution of 4-Bromo-1-[4-(3-chloro-4-fluoro-phenylamino)-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluoren-7-yl]-but-2-en-1-one (0.125 g, 0.00026 mol) in dichloromethane (1.25 ml) was added dimethylamine (2.0M solution in THF) (0.65 ml, 0.001 mol) over 1-2 min. The resulting mixture was stirred at RT for 2 hours. TLC (10% MeOH/Dichloromethane) indicates no SM present, a new polar spot seen. Conc. the reaction mixture to dryness under vacuum at 30° C. Purified by silica gel chromatography (ISCO system) using a gradient of dichloromethane—30% methanol/dichloromethane. The fractions combined, conc to dryness and the residue dissolved in 10% MeOH/DCM, filtered through a filter paper. The filterate was conc. to dryness and dried under vacuum at RT O/N to give 0.03 g (23%) of desired product. 1H-NMR (CD3OD-d3) δ 8.46 (m, 1H), 8.39 (s, 1H), 7.88 (m, 1H), 7.62 (m, 1H), 7.42 (t, 1H), 6.67 (m, 1H), 3.94 (m, 2H), 3.87 (m, 4H), 2.75 (m, 2H), 2.56 (s, 6H); LCMS RT=2.38 min, [M+H]+=446.0.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][S:8][CH2:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[ClH:23]>C(Cl)Cl>[N:10]1([C:4]2[C:5]3[CH2:9][S:8][CH2:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[ClH:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2CSC3)CC1
Agent: Cl
Solvent: ClCCl
Product: c1nc2c(c(N3CCNCC3)n1)CSC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.41 g, 1.3 mmol) in CH2Cl2 (20 mL) was added HCl (4M in dioxane, 5 mL). The mix was stirred at room temperature for 4 hours. The solvent was removed to afford 4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine as HCl salt (0.28 g, 99%). MS (APCI+) [M+H]+ 223.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]2Cl)=[CH:13][C:6]=1[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[C:30](O)(=[O:32])C>CO>[Cl:4][C:5]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]2[O:32][CH3:30])=[CH:13][C:6]=1[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
51.3 ml of a 2N solution of sodium methylate in methanol are added dropwise while stirring and cooling at 0° C. during 5 minutes to a solution of 42.4 g of isopropyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate in 100 ml of absolute methanol. The reaction mixture is stirred at 0° C. for 10 minutes and adjusted to about pH 4 with concentrated acetic acid. Subsequently, the reaction mixture is evaporated to dryness under reduced pressure. The residue is dissolved in 300 ml of diethyl ether and the solution is washed twice with 100 ml of water each time. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column using n-hexane/diethyl ether (3:1) as the eluent and is subsequently recrystallized from n-hexane/diethyl ether. There is obtained isopropyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoate, m.p. 121°-123° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Br:17].[I:18]I>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([I:18])[C:11]=1[Br:17]
Reactant: Fc1ccc(Br)c(Br)c1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(Br)c(Br)c1I
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of freshly-prepared LDA (33.9 mmol) in anhyd THF (100 mL) at −78° C. was added a solution of 1,2-dibromo-4-fluorobenzene (4 mL, 32.3 mmol) in THF (8 mL), dropwise at such a rate that the internal temperature remained <−70° C. The mixture was stirred 30 min and iodine (9.02 g, 35.5 mmol) was added in one portion. The mixture was stirred 30 min, quenched by addition of 10% Na2S2O3, and removed from the cooling bath. Upon warming the mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was eluted from a pad of silica (hexanes→2% EtOAc/hexanes) and recrystallized from MeOH-water affording 1,2-dibromo-4-fluoro-3-iodobenzene (8.59 g, 70% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J=8.8, 5.5 Hz, 1H), 6.93 (dd, J=8.8, 7.0 Hz, 1H); MS (GCMS EI) m/z 378 ([M]+, Br isotopes, 56%), 380 ([M]+, Br isotopes, 100%), 382 ([M]+, Br isotopes, 51%).
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](Cl)=[O:7])=[N+:2]=[N-:3].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].O>ClCCCl>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])=[O:7])=[N+:2]=[N-:3]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CCNCC
Solvent: O
Solvent: ClCCCl
Product: CCN(CC)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutanoyl chloride (8.00 g, 49.5 mmol) in anhydrous DCE (160 mL) was added diethylamine (15.4 mL, 3 equiv, 0.148 mol) in one portion. The reaction was left to stir at 0° C. for 1 h. Water (200 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with water (3×100 mL) and brine (100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (9.80 g, quant). This material was used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH2:12]([Mg]Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.O1CCCC1>[NH2:11][C:10]1[CH:9]=[C:8]2[C:3](=[C:1]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:2]=1)[N:4]=[CH:5][CH:6]=[CH:7]2
Reactant: N#CCc1cccnc1C#N
Reactant: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1cc2cccnc2c(Cc2ccccc2)n1

Procedure:
To a solution of 2-cyano-3-pyridylacetonitrile (2 g, 0.014 mol) in toluene (20 ml) is added benzylmagnesium bromide 8.4 ml, 2N in tetrahydrofuran, 0.17 mol) at ambient temperature. After 1 h the reaction is quenched with a saturated solution of ammonium chloride. The product is extracted with ethyl acetate and the organic layer washed with 2N NaOH and water. The product is purified by flash column chromatography on silica gel (10:3 toluene/acetone) affording the title compound. Mass M+H 236; mp 113-116° C.
Reaction SMILES: C(SC=C)=C.CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C.O=O.II.OO.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(S[C:53]1([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([OH:72])[CH:67]=2)[C:56]2([CH:63]3[CH2:64][CH:59]4[CH2:60][CH:61]([CH2:65][CH:57]2[CH2:58]4)[CH2:62]3)[O:55][O:54]1)C.[O:73]1[CH2:76]CO1>CO.CCCCCC.CS(C)=O.C(OCC)(=O)C>[OH:72][C:68]1[CH:67]=[C:66]([C:53]2([O:73][CH3:76])[C:56]3([CH:57]4[CH2:65][CH:61]5[CH2:60][CH:59]([CH2:64][CH:63]3[CH2:62]5)[CH2:58]4)[O:55][O:54]2)[CH:71]=[CH:70][CH:69]=1
Reactant: C1COO1
Reactant: CCSC1(c2cccc(O)c2)OOC12C1CC3CC(C1)CC2C3
Agent: C=CSC=C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC1(c2cccc(O)c2)OOC12C1CC3CC(C1)CC2C3
Temperature: 25 °C

Procedure:
The vinyl sulfide of Example 1(b) (0.113 g) was irradiated for 15 min in 20 mL of methanol containing a few crystals (<1 mg) of methylene blue with continuous oxygen bubbling at -78° C. using a 1000 W Na lamp. Iodine (0.096 g) and 1 mL of 30% H2O2 were added and the mixture warmed to room temperature. Progress of the reaction was monitored by the disappearance of starting material by TLC (20% ethyl acetate in hexane) and the appearance of new bands which emitted blue light when the plate was heated and by observing the color of chemiluminescence from an aliquot of the reaction solution reacted with 0.1 M TBAF in DMSO. The yellow emission of dioxetane 1 was gradually replaced by the blue emission of dioxetane 6 over a period of several hours. The solution was concentrated to 1-2 mL and separated on preparative TLC with 10% ethyl acetate in hexane. The band containing dioxetane 6 was collected, desorbed and evaporated yielding 77 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@@H:11]2[C@@H:15]([OH:16])[C@H:14]([CH2:17][OH:18])[O:13][CH2:12]2)=[CH:5][CH:4]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:18][CH2:17][C@@H:14]2[O:13][CH2:12][C@H:11]([S:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C@H:15]2[OH:16])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(CS[C@H]2CO[C@@H](CO)[C@@H]2O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(CS[C@H]2CO[C@@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a 0° C. solution, under argon, of 0.580 g of product from Example 323 in 10 ml of pyridine is added 0.430 g of p-toluenesulfonyl chloride. The reaction is stirred at room temperature overnight. The mixture is quenched with water, extracted with diethyl ether, washed with water and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (Silica gel: 50% ethyl acetate/hexane) to give 0.520 g of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[Cl:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.O>C1COCC1>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([O:11][C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[CH:13][CH:14]=2)[C:25]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: Cn1c(Oc2ccc(N)cc2)nc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(Oc2ccc(Nc3ncnc(Cl)c3[N+](=O)[O-])cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
To a solution of 4-[(1-methyl-1H-benzimidazol-2-yl)oxy]aniline (0.30 g) and TEA (0.26 mL) in THF (15 mL) was added 4,6-dichloro-5-nitropyrimidine (0.24 g) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, silica gel, eluted with 5%-50% AcOEt in hexane) to give 6-chloro-N-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-5-nitropyrimidin-4-amine (0.24 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([CH3:14])=[CH:16][C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Cc1cc2c(s1)CCNC2C
Product: Cc1cc2c(s1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C
Yield: 46 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,4-dimethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:34]([CH3:36])[CH3:35]>C(OCC)(=O)C.CCCCCC.O>[CH:34]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)([CH3:36])[CH3:35]
Reactant: CC(C)Br
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 6-hydroxy-2-piperonylidene 3(2H)-benzofuranone 0.5 g, potassium carbonate 0.58 g and dimethylformamide 5 ml, 2-bromopropane 0.306 g was added. After the mixture was refluxed for 2.5 hours, water 50 ml was added. The resulting compound was extracted with ethyl acetate 50 ml twice. The ethyl acetate solution was washed with a saturated sodium chloride solution 50 ml twice, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The crude extract was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dissolved in ethyl acetate 5 ml and hexane 10 ml, and the solution was allowed to stand at room temperature for two hours. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 519.6 mg.
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH:5]([CH3:7])[CH3:6].[CH2:9]([Si:15](Cl)([Cl:17])[Cl:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(OCC)C.CCCCCC.O1CCCC1>[CH2:9]([Si:15]([CH2:4][CH:5]([CH3:7])[CH3:6])([Cl:17])[Cl:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC[Si](Cl)(Cl)Cl
Reactant: CC(C)CBr
Agent: II
Agent: [Mg]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC[Si](Cl)(Cl)CC(C)C

Procedure:
Anhydrous diethyl ether (125 mL) was put into a reactor with magnesium (5.0 g, 0.21 mol) which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. i-Butylbromide (25 g, 0.18 mol) was added dropwise to the slowly stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing n-hexyltrichlorosilane (64 g, 0.25 mol) in anhydrous diethyl ether (50 mL)/anhydrous tetrahydrofuran (50 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 50° C.-60° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20])([CH3:15])([CH3:14])[CH3:13].Cl[CH2:23][CH2:24][S:25][CH2:26][CH2:27]Cl>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17]([C:18]1([C:19]#[N:20])[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1)=[O:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: ClCCSCCCl
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C1(C#N)CCSCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-hydroxy-ethylsulfanyl)-ethanol (13.17 g), thionyl chloride (24 mL) in DCM (250 mL) was stirred in an ice/water bath overnight. Then the reaction mixture was concentrated to give crude product 1-chloro-2-(2-chloro-ethylsulfanyl)-ethane (100%), which was used directly in the next step. DBU (42.04 mL) was added slowly to a solution of cyano-acetic acid tert-butyl ester (13.23 g) and 1-chloro-2-(2-chloro-ethylsulfanyl)-ethane (all the crude from previous step) in DMF (200 mL) at rt and then the reaction mixture was stirred in an oil bath (bath temperature=80° C.) overnight. The reaction was cooled, diluted with EtOAc, then washed with cold water, dil. NaCl solution; EtOAc phase was dried over anhydrous sodium sulfate, filtered, concentrated; the residue was column purified to give title compound (7.961 g). 1H NMR in CDCl3, δ in ppm: 3.1-2.9 (m, 2H), 2.7-2.5 (m, 2H), 2.45-2.35 (m, 2H), 2.2-2.1 (m, 2H), 1.51 (s, 9H).