Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:28]=[O:29])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[CH:20]=[N:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[CH:20]=[N:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=4[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:28]([OH:29])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: COc1cc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)cn1
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(OC)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.23 mL, 0.69 mmol) was added to a stirred solution of 9-chloro-1-(6-methoxy-4-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (207 mg, 0.580 mmol) in tetrahydrofuran (5.0 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (141 mg, 0.364 mmol, 63%).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1B(O)O)=[O:2].Br[C:12]1[CH:16]=[CH:15]S[C:13]=1[CH:17]1OCCO1.[CH2:22]([Li])CCC.B(OCCCC)(OCCCC)OCCCC>BrC1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>[C:13]1([C:7]2[CH:6]=[CH:5][S:4][C:3]=2[CH:1]=[O:2])[CH:12]=[CH:16][CH:15]=[CH:22][CH:17]=1
Reactant: Brc1ccsc1C1OCCO1
Reactant: O=Cc1sccc1B(O)O
Reactant: [Li]CCCC
Agent: CCCCOB(OCCCC)OCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Brc1ccccc1
Product: O=Cc1sccc1-c1ccccc1

Procedure:
3-bromothiophen-2-aldehyde (2) was obtained from commercially available 2,3-dibromothiophen (1) via 3-bromothienyllithium and reaction with N,N-dimethylformamide. The aldehyde 2 was protected by reaction with ethylene glycol to give 2-(3-bromo-2-thienyl)-1,3-dioxolane (3). The latter derivative was converted into 2-formyl-3-thiopheneboronic acid (4) using halogen-metal interconversion between the substrate (3) and butyllithium at −70° C., followed by treatment with tributyl borate and subsequent hydrolysis. The thienylboronic derivative 4 is a very useful intermediate, in fact it can be condensed with various bromo-aromatic compounds. Thus, palladium-catalysed condensation reaction of the derivative 4 with bromobenzene in aqueous sodium carbonate-ethanol mixture as solvent gave 3-phenyl-thiophen-2-carboxaldehyde (5). Oxidation of 5 with Jones' reagent yielded 3-phenyl-thiophen-2-carboxylic acid (6). Chlorination of 6 with thionyl chloride followed by reaction with sodium azide yielded the acyl azide intermediate which on thermolysis in boiling o-dichlorobenzene gave the derivative thieno[2,3-c]isoquinolin-5(4H)-one (7).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])(=[O:25])=[O:24].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:30]([C:29]4[CH:28]=[C:27]([NH:26][S:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)(=[O:24])=[O:25])[CH:35]=[CH:34][CH:33]=4)=[O:31])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccccn2)c1
Reactant: Clc1ccc2nc(N3CCNCC3)oc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1cccc(NS(=O)(=O)c2ccccn2)c1)N1CCN(c2nc3ccc(Cl)cc3o2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Compound 10 is prepared using synthesis method 2: intermediate 3b (0.16 g, 0.67 mmol) is placed in 21 mL of acetonitrile in the presence of 0.18 g (0.67 mmol) of intermediate 5a and 103 μL of Et3N. 0.21 g (0.67 mmol) of TBTU is then added and the mixture is then stirred for 5 h at ambient temperature. After evaporation under reduced pressure the residue is taken up by water and extracted using AcOEt. After the organic phases are dried and after reduction to dryness the residue obtained is purified by flash chromatography (CH2Cl2-MeOH, gradient 99-1 to 95-5 over 65 min). 0.23 g of solid is obtained (yield: 68%).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH:9]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[I:21][C:22]1[C:27]([CH2:28][O:29][CH2:30][CH:31]2C[O:32]2)=[C:26]([I:34])[C:25]([CH2:35][O:36][CH2:37][CH:38]2[CH2:40][O:39]2)=[C:24]([I:41])[C:23]=1[CH2:42][O:43][CH2:44][CH:45]1[CH2:47][O:46]1.Cl>C1(C)C=CC=CC=1>[I:34][C:26]1[C:25]([CH2:35][O:36][CH2:37][CH:38]([OH:39])[CH2:40][N:9]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:24]([I:41])[C:23]([CH2:42][O:43][CH2:44][CH:45]([OH:46])[CH2:47][N:9]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:22]([I:21])[C:27]=1[CH2:28][O:29][CH2:30][CH:31]([OH:32])[CH2:6][N:4]1[CH2:3][CH2:17][NH:18][CH2:19][CH2:20][NH:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:5]1
Reactant: COC(OC)N(C)C
Reactant: Ic1c(COCC2CO2)c(I)c(COCC2CO2)c(I)c1COCC1CO1
Reactant: C1CNCCNCCNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Product: OC(COCc1c(I)c(COCC(O)CN2CCNCCNCCNCC2)c(I)c(COCC(O)CN2CCNCCNCCNCC2)c1I)CN1CCNCCNCCNCC1
Temperature: 25 °C

Procedure:
10 ml (75.28 mmol) of N,N-dimethylformamide dimethyl acetal is added to 10 g (58.05 mmol) of 1,4,7,10-tetraazacyclododecane, dissolved in 100 ml of toluene, and it is heated for 2 hours to 120° C. under nitrogen. In this case, a methanol/toluene azeotrope is distilled off continuously. Then, the reaction mixture is concentrated by evaporation at 70° C. in a vacuum, 13.6 g (19.1 mmol) of 1,3,5-triiodo-2,4,6-tris-(oxiranylmethoxymethyl)benzene is added, and it is heated under nitrogen for 24 hours to 110° C. After cooling to room temperature, it is mixed with 100 ml of 2N HCl and then heated for 12 hours to 80° C. It is evaporated to the dry state, mixed with 50 ml of ethanol and 50 ml of methanol and evaporated to the dry state again. The residue is dissolved in 100 ml of ethanol while being heated, and then slowly cooled to 0° C., whereby a white solid crystallizes out. The solid is filtered off, washed with ethanol and then dried at 50° C. in a vacuum. The solid is dissolved in 100 ml of water and 100 ml of dichloromethane, and 32% NaOH solution is added while being stirred vigorously until a pH of 10 is reached. The organic phase is separated, the aqueous phase is extracted three times with 100 ml each of dichloromethane, the combined organic phases are dried on magnesium sulfate and evaporated to the dry state.
Reaction SMILES: [Cl:1][CH:2]([C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([O:5][CH3:6])=[O:4].P.C(Cl)Cl>[Ru].CO>[Cl:1][CH:2]([C@H:7]([OH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCCCCCCC(=O)C(Cl)C(=O)OC
Agent: [Ru]
Agent: P
Solvent: ClCCl
Solvent: CO
Product: CCCCCCC[C@@H](O)C(Cl)C(=O)OC
Yield: 95 %

Procedure:
In a 500 ml Hastelloy-made autoclave having been purged with nitrogen were put 100 g (0.426 mol) of the methyl 2-chloro-3-oxodecanoate (VII) prepared in (1) above, 5 ml of a methylene chloride solution of 780 mg (0.426 mmol) of a ruthenium-optically active phosphine complex Ru2Cl4 [(+)-Tol-BINAP]2NEt3, and 300 ml of methanol, and the mixture was allowed to react at 50° C. under a hydrogen pressure of 30 atm for 18 hours. Methanol was removed by evaporation to yield 95.78 g (0.405 mol; yield: 95.0%) of the title compound.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[CH2:13][N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>CC(O)=O.CO.[OH-].[OH-].[Pd+2]>[CH3:17][C:14]1([CH3:18])[CH2:13][NH:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:16][O:15]1
Reactant: CC1(C)CN(Cc2ccccc2)C(C(=O)OCc2ccccc2)CO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CNC(C(=O)O)CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.4 %

Procedure:
To a solution of 4-benzyl-6,6-dimethyl-morpholine-3-carboxylic acid benzyl ester (Intermediate 18, 1.25 g) in 40 ml of 10% AcOH/MeOH (under nitrogen) was added 250 mg of 20% Pd(OH)2 on charcoal. The reaction mixture was purged with hydrogen (balloon) and was stirred at ambient temperature for 72 hrs. To the resulting gray mixture was added 4 ml of water to help dissolution. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was co-evaporated with ethanol (2×) and then triturated with EtOAc. The generated white solid was filtered off and dried under high vacuum to give 559 mg of 6,6-dimethyl-morpholine-3-carboxylic acid (95% yield).
Reaction SMILES: C([O:4][CH:5]([CH3:38])[C:6]([N:8]([CH2:32][CH2:33][O:34]C(=O)C)[C:9]1[C:10]([I:31])=[C:11]([C:17]([I:30])=[C:18]([NH:21][C:22](=[O:29])[CH:23]([O:25]C(=O)C)[CH3:24])[C:19]=1[I:20])CCC([O-])=O)=[O:7])(=O)C.[OH-:39].[Na+].Cl.[CH3:42]O>O>[OH:4][CH:5]([CH3:38])[C:6]([N:8]([CH2:32][CH2:33][OH:34])[C:9]1[C:10]([I:31])=[C:11]([C:17]([I:30])=[C:18]([NH:21][C:22](=[O:29])[CH:23]([OH:25])[CH3:24])[C:19]=1[I:20])[CH2:42][OH:39])=[O:7]
Reactant: CO
Reactant: CC(=O)OCCN(C(=O)C(C)OC(C)=O)c1c(I)c(CCC(=O)[O-])c(I)c(NC(=O)C(C)OC(C)=O)c1I
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(O)C(=O)Nc1c(I)c(CO)c(I)c(N(CCO)C(=O)C(C)O)c1I
Reaction time: 2 h

Procedure:
N,N'-Bis(2-acetoxypropionyl)-N-(2-acetoxyethyl)-3,5-diamino-2,4,6-triiodobenzylacetate (120 mg, 0.14 mmol) was dissolved in a mixture of water (7 ml) and methanol (7 ml) and pH was adjusted to 12 using an 1M aqueous solution of NaOH. The mixture was stirred for 2 h, pH was adjusted to 7 with aqueous HCl and the solvents were evaporated. The product was purified by preparative HPLC. Yield: 70 mg (72%).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([CH3:35])[C:15](=[O:34])[CH2:16][C:17]2[C:18]([CH3:33])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH:9]=1)[CH3:6])C.[Li+].[OH-]>C1COCC1.CO>[CH3:36][C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([CH3:35])[C:15](=[O:34])[CH2:16][C:17]2[C:18]([CH3:33])=[N:19][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[CH:9]=1)([CH3:6])[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N(C)C(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)N(C)c1cccc(OC(C)(C)C(=O)O)c1
Reaction time: 6 h

Procedure:
0.50 g (0.97 mmol) of the above prepared 2-methyl-2-[3-(methyl-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-amino)-phenoxy]-propionic acid ethyl ester was dissolved in 15 ml of THF/MeOH=2:1. To the stirred solution was added 1.16 ml of a LiOH-solution (1 molar in water). After 6 hours, the reaction mixture was poured into crashed ice/HCl and extracted twice with CH2Cl2; the organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated to give 0.47 g of pure title compound as colorless foam.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][O:10][C:11]1[C:16]2[C:17](=[O:27])[N:18]3[CH2:25][C@H:24]([OH:26])[CH2:23][C@H:19]3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=[CH:13][C:12]=1[O:28][CH3:29].N1C=CN=C1.O>CN(C=O)C>[CH3:9][O:10][C:11]1[C:16]2[C:17](=[O:27])[N:18]3[CH2:25][C@H:24]([O:26][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23][C@H:19]3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=[CH:13][C:12]=1[O:28][CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Solid TBDMS Chloride (8.22 g, 54.44 mmol) was added in one portion to a solution of 170 (7.23 g, 24.74 mmol) and imidazole (8.42 g, 123.72 mmol) in anhydrous DMF (75 mL) and allowed to stir at room temperature for 16 h. The reaction mixture was poured into water (500 mL) and filtered to afford the crude product (171), which was purified by recrystallisation from EtOH (800 mL) as fine white needles (6.995 g, 17.21 mmol, 70%). 1HNMR (270 MHz, CDCl3) δ 10.06 (s, 1H, NH), 7.37 (S, 1H, ArH), 6.68 (s, 1H, ArH), 4.19-4.14 (m, 1H, 2), 4.06-4.01 (m, 1H, 11a), 3.90 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.69-3.63 (m, 2H, 3), 2.85-2.80 (m, 1H, 1), 2.05-2.01 (m, 1H, 1); 13C NMR (67.8 MHz, CDCl3) δ 170.4, 170.2, 165.9, 152.1, 145.8, 145.6, 131.1, 130.7, 118.1, 111.9, 104.3, 104.1, 69.2, 69.1, 56.0, 55.9, 55.7, 54.3, 54.0, 35.0, 25.8, 25.7, 25.6, 17.9, −3.0, −3.5, −4.9, −5.0.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19]C(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[C:28]([CH3:33])[N:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:18]([OH:24])=[O:19].[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[CH:6]=[C:5]([NH:25][C:26]2[CH:31]=[C:30]([OH:32])[CH:29]=[C:28]([CH3:33])[N:27]=2)[C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=1
Reactant: Cc1cc(O)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(O)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C(N)=O)n1
Product: O=CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [(1S,2R)-2-({6-carbamoyl-5-[(4-hydroxy-6-methylpyridin-2-yl)amino]pyridin-3-yl]amino)cyclohexyl}carbamate (32 mg, 0.070 mmol) in DCM (2 ml) was added TFA (1.0 mL, 13 mmol), and the reaction mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was concentrated under reduced pressure, dissolved in DMSO (1 mL), and purified by reverse phase HPLC (acetonitrile/water with 0.1% formic acid, linear gradient) to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(4-hydroxy-6-methylpyridin-2-yl)amino]pyridine-2-carboxamide formic acid salt. MS ESI calc'd. for C18H25N6O2 [M+H]+ 357. found 357. 1H NMR (500 MHz, CD3OD) δ 8.10 (s, 1H), 7.85 (s, 1H), 7.40 (s, 1H), 6.39 (s, 1H), 6.25 (s, 1H), 3.95 (br s, 1H), 3.56 (br s, 1H), 2.38 (s, 3H), 1.90-1.82 (m, 3H), 1.80-1.62 (m, 3H), 1.60-1.50 (m, 2H).
Reaction SMILES: [Cl:1]/[C:2](=[C:6](\[Cl:10])/[C:7](O)=[O:8])/[C:3](O)=[O:4].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>O>[F:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]2[C:3](=[O:4])[C:2]([Cl:1])=[C:6]([Cl:10])[C:7]2=[O:8])=[CH:14][CH:13]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)/C(Cl)=C(/Cl)C(=O)O
Solvent: O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(F)cc1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
10 g (0.06 mol) of 2,3-dichloromaleic acid was dissolved in 100 ml of water. Then, to the resulting solution 5.55g (0.05 mol) of 4-fluoroaniline was added dropwise over a period of 5 min. at reflux temperatures under agitation. Upon addition of 4 -fluoroaniline, a white crystal separated out immediately but the reaction was allowed to preceed for two hours. After cooling, the crystal was separated by filtration and fully rinsed with water to obtain 12.7g (yield, 97.7%) of N-(4-fluorophenyl)-2,3-dichloromaleimide (Sample No. 1) having an average grain size of 10μ. An analysis by gas chromatography showed that the N-(4-fluorophenyl)-2,3-dichloromaleimide had a purity of 96.2%.
Reaction SMILES: [CH2:1]([C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9](OC(CC)C)=[CH:8][C:7]=1[OH:19])[CH:2]=[C:3]([CH3:5])[CH3:4].IN1C(=O)[CH2:24][CH2:23][C:22]1=[O:27].Cl[CH2:29]Cl>O>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([O:27][CH:22]([CH2:23][CH3:24])[CH3:29])=[C:7]2[C:6]=1[CH:1]=[CH:2][C:3]([CH3:4])([CH3:5])[O:19]2
Reactant: CCC(C)Oc1cc(O)c(CC=C(C)C)c(OC)c1
Reactant: O=C1CCC(=O)N1I
Reactant: ClCCl
Solvent: O
Product: CCC(C)Oc1ccc(OC)c2c1OC(C)(C)C=C2
Temperature: 30 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
5.8 g (22 millimoles) of 2-prenyl-3-methoxy-5-sec.butoxy-phenol are dissolved in 100 ml of dichloro methane, whereupon 5 g (22 millimoles) of N-iodo-succinimide are added. The reaction mixture is stirred at 30° C. for 1 hour, diluted with 200 ml of water, the organic phase is separated washed with a 5% sodium thiosulfate solution, dried and evaporated. The residue is dissolved in 100 ml of a 10% methanolic sodium hydroxide solution and allowed to stand at 50° C. for 2 hours. The solution is diluted with water and extracted with ether. The organic phase is washed subsequently with a 1% hydrochloric acid solution and water, the solvent is removed and the product purified as described in Example 3. Thus 5.5 g of the desired compound are obtained in the form of a light yellow oil. Yield: 95%.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.O>CS(C)=O>[O:18]1[CH2:4][CH:17]1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2[S:8][CH:12]=[CH:11][N:10]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(-c2nccs2)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1csc(-c2ccc(C3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a suspension of 0.063 g (1.5 mmol) of sodium hydride in DMSO (10 mL) was added 0.300 g (1.47 mmol) of trimethylsulfonium iodide as a solution in DMSO (5 mL). After stirring at room temperature for 5 min 0.130 g (0.687 mmol) of the above aldehyde was added as a solution in DMSO (5 mL). The mixture was allowed to stir at room temperature for 2 h. The mixture was poured into H2O and washed with EtOAc. The combined organic phase was washed with H2O, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.129 g (92.3%) of 2-(4-oxiranyl-phenyl)-thiazole as a clear oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:25])[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([OH:24])=[CH:9][CH:10]=2)[O:5]1.Cl[CH2:27][C:28]#[N:29]>CN(C)C=O>[C:28]([CH2:27][O:24][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=3)[CH2:13][C:4]([CH3:25])([CH3:3])[O:5]2)=[CH:10][CH:9]=1)#[N:29]
Reactant: N#CCCl
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC#N)cc2O1
Temperature: 60 °C

Procedure:
Sodium hydride (0.93 g, 80% dispersion in oil) was added to a solution of 2,2-dimethyl-4-(3-trifluoromethylphenyl)chroman-7-ol (containing 1 mole of carbon tetrachloride of crystallisation) (7.5 g) in dimethylformamide (25 ml). Chloroacetonitrile (1.76 g) was added and the mixture heated at 60° C. for 3 hours. The solvent was removed under reduced pressure and the resulting oil was poured into water. The aqueous solution was extracted with ether and the etheeal extracts were dried (MgSO4) and evaporated under reduced pressure to yield an oil. Chromatography on alumina with ether-petrol (40°-60° C.), 1:3 as eluate gave the title compound which crystallised on standing.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:4]=2[N:3]=1.C(N(CC)CC)C.Cl[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28].O>ClCCl>[Cl:1][C:2]1[N:6]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:5]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:4]=2[N:3]=1
Reactant: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)CCOCn1c(Cl)nc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-chloro-5-trifluoromethyl-1H-benzoimidazole (1 g, 4.52 mmol, Example 1 c), triethylamine (1.3 mL, 9.04 mmol, Aldrich) and (2-chloromethoxy-ethyl)-trimethyl-silane (881 μL, 4.98 mmol, Aldrich) in dichloromethane (30 mL) was stirred at room temperature for 16 h. Water (150 mL) was added, and the mixture was extracted with dichloromethane (2×150 mL). The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with hexane/EtOAc (10:1) to give the title compound as an orange solid. MS (ESI, positive ion) m/z: 351 (M+1).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[N:24][C:9]=3[O:10][C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:2]([F:1])([F:29])[C:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[N:24][C:9]=3[O:10][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1c(C(F)(F)F)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc2n1-c1cccnc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a solution of tert-butyl 9′-(trifluoromethyl)spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (83 mg, 0.20 mmol) in CH2Cl2 (3 mL) was added TFA (1.0 mL, 13 mmol) and the mixture was stirred at room temperature for 15 min before being evaporated to dryness. The residue was taken up in EtOAc and sat. aq. Na2CO3, the layers were separated, and aqueous layer was extracted with EtOAc (2×). The organics were combined, washed with sat. aq. Na2CO3, brine, dried (Na2SO4) and evaporated to dryness to give 9′-(trifluoromethyl)-spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine] as a pale yellow solid (59 mg). ESI-MS m/z calc. 309.1. found 310.3 (M+1)+; Retention time: 1.32 minutes (3 min run).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>C1COCC1>[C:1]1([CH:7]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([B:23]([OH:28])[OH:24])=[CH:14][C:13]=3[CH:17]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)c1ccc2occc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(c1ccccc1)c1ccc2oc(B(O)O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(1-phenylethyl)benzofuran (0.713 g, 3.21 mmol) in 32 mL THF at −78° C. was added 1-butyllithium (1.54 mL, 3.85 mmol) slowly dropwise. The reaction was allowed to stir for 25 min, at which point triisopropyl borate (1.08 mL, 4.72 mmol) was added slowly dropwise. After 0.5 h, the bath was removed and the reaction was allowed to warm to ambient temperature. After 0.5 h, 50 mL 2N HCl was added. The mixture was extracted 2×MTBE, and the combined organics were washed with brine, dried over anhyd. sodium sulfate, filtered, and concentrated in vacuo to give an oil. Treatment with 30 mL hexanes and sonication for 5 min resulted in a white solid which was collected by filtration and dried in vacuo to give 5-(1-phenylethyl)benzofuran-2-ylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49-8.57 (m, 2H), 7.58 (s, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.40 (s, 1H), 7.12-7.32 (m, 6H), 4.26 (q, J=7.5 Hz, 1H), 1.62 (d, J=7.0 Hz, 3H).