Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:5]=[C:6]([F:11])[C:7]=1[O:8][CH2:9][CH3:10].C([Sn](CCCC)(CCCC)[C:34]([O:36]CC)=[CH2:35])CCC.Cl.C(=O)([O-])O.[Na+]>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>[C:34]([C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:5]=[C:6]([F:11])[C:7]=1[O:8][CH2:9][CH3:10])(=[O:36])[CH3:35]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOc1c(F)cc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CCOc1c(F)cc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1C(C)=O
Temperature: 110 °C
Reaction time: 5 h

Procedure:
To a mixture of N-((2S)-1-((2-(3-bromo-4-ethoxy-5-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (1.50 g) and toluene (10 mL) were added tributyl(1-ethoxyvinyl)stannane (2.25 mL) and tetrakis(triphenylphosphine)palladium(0) (192 mg), and the mixture was stirred at 110° C. for 5 hr under an argon atmosphere. To the reaction mixture was added 0.5N hydrochloric acid, and the mixture was stirred at room temperature for 1 hr, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained solid was washed with diethyl ether-hexane to give the title compound (1.22 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([O:17][CH2:18][CH2:19][O:20][C:21]2[N:26]=[CH:25][C:24]([Br:27])=[CH:23][N:22]=2)[N:5]=[C:4]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[N:3]=1.[H-].[Na+].[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[S:41](Cl)(=[O:43])=[O:42].[Cl-].[NH4+]>O1CCCC1>[Br:27][C:24]1[CH:23]=[N:22][C:21]([O:20][CH2:19][CH2:18][O:17][C:6]2[N:5]=[C:4]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:3]=[C:2]([NH:1][S:41]([C:37]3[S:36][CH:40]=[CH:39][CH:38]=3)(=[O:43])=[O:42])[C:7]=2[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[N:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1OCCOc1ncc(Br)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2cccs2)nc(-c2ncccn2)nc1OCCOc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
A mixture of 4-amino-6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine (100 mg), sodium hydride (60 dispersion, 53.5 mg) and tetrahydrofuran (3 ml) is stirred at room temperature for 20 minutes. To the mixture is added thiophenesulfonyl chloride (23.4 mg), and the mixture is stirred for 22 hours. The reaction solution is treated with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by preparative thin layer chromatography (solvent; chloroform: methanol=10:1) to give the title compound (49.1 mg).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@:17]1([C:27]([OH:29])=[O:28])[CH2:22][C:21](=[O:23])[C@@H:20]2[C@H:18]1[C@H:19]2[C:24]([OH:26])=[O:25])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:9]([O:13][C:14]([NH:16][C@@:17]1([C:27]([O:29][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:28])[CH2:22][C:21](=[O:23])[C@@H:20]2[C@H:18]1[C@H:19]2[C:24]([O:26][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:25])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)CC(=O)[C@H]2[C@H](C(=O)O)[C@H]21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2)CC(=O)[C@H]2[C@H](C(=O)OCc3ccccc3)[C@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Add benzyl bromide (8.69 mL, 72.9 mmol) dropwise to a stirred suspension of (1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (7.27 g, 24.3 mmol) and cesium carbonate (15.83 g, 48.6 mmol) in dry N,N-dimethylformamide (60 mL). Stir the resulting mixture at room temperature overnight under nitrogen. Quench with water and dilute with ethyl acetate. Extract the aqueous phase with ethyl acetate (3 times) and wash the organic layers with brine and water. Dry over sodium sulfate, filter and concentrate to give the crude material as a pale brown oil. Purify by flash chromatography eluting with ethyl acetate:hexane (20:80 to 30:70) to give the title compound as gummy yellow foam (9.15 g, 78.5%). MS (m/z): 502 (M+23).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].CN(C)C=O.CO[C:17](OC)([CH3:19])[CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:18][C:17]1([CH3:19])[O:5][CH2:4][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: OCC(CO)(CO)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CO)(CO)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 5 L round-bottom flask fitted with a thermometer, a nitrogen-introducing tube, and a stirrer were charged 254 g of pentaerythritol and 2,500 g of N,N-dimethylformamide, and they were heated and dissolved at 80° C. After cooling to 25° C., 195 g of 2,2-dimethoxypropane and 3.6 g of p-toluenesulfonic acid monohydrate were placed therein and, with introduction of nitrogen thereinto, a reaction was carried out at 25° C. without further treatment. Neutralization was performed by adding 9.5 g of triethylamine and the reaction solution was concentrated. After concentration, the resulting powder was dispersed in 1 kg of hexane, followed by stirring and filtration. The hexane-washing step was repeated four times. The resulting cake was dissolved in 1 kg of ethyl acetate at 50° C. and, after insoluble matter was filtrated, 250 g of Kyoward 2003 was added to the filtrate and adsorption treatment was performed at 50° C. for 1 hour. The filtrate was concentrated to obtain 2,2-dimethyl-5,5-bis(hydroxymethyl)-1,3-dioxane. 1H-NMR (D2O, internal standard H2O=4.65 ppm) δ (ppm): 1.40 (6H, s, —CH3), 2.69, 3.64 (4H, 4H, s, s, —O—CH2—C—, —CH2OH)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](C)([CH3:14])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][C:9]=3[O:23][C:4]=2[CH:3]=1.IC1C=CC2C(C(C)(C)CN)=COC=2C=1.IC1C=CC2C(C(C)C#N)=COC=2C=1>>[C:19]([O:18][C:16]([N:11]1[CH2:12][CH:13]([CH3:14])[C:8]2[C:5]3[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=3[O:23][C:9]=2[CH2:10]1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1Cc2oc3cc(I)ccc3c2C(C)(C)C1
Agent: CC(C#N)c1coc2cc(I)ccc12
Agent: CC(C)(CN)c1coc2cc(I)ccc12
Product: CC1CN(C(=O)OC(C)(C)C)Cc2oc3cc(I)ccc3c21

Procedure:
Synthesized as described for tert-butyl 7-iodo-4,4-dimethyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate using 2-(6-Iodo-benzofuran-3-yl)-propionitrile 2-(6-Iodo-benzofuran-3-yl)-2-methyl-propylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[C:3]=1[C:4]#[N:5].[S:24](Cl)(=[O:27])(=[O:26])[NH2:25]>>[S:24]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[C:4]#[N:5])(=[O:27])(=[O:26])[NH2:25]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCCCOc1cccc(N)c1C#N
Product: N#Cc1c(NS(N)(=O)=O)cccc1OCCCCCO
Yield: 4 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(5-(tert-butyldimethylsilyloxy)pentyloxy)benzonitrile (Example 241b) and sulfamoyl chloride in 4% yield. MS 300 (MH+).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:14](Cl)=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[S:13]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:14]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:15]
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 2-thenoyl chloride (1.466 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 8 hours. The reaction mixture was treated in the same manner as described in Example 35 to obtain 965 mg of the title compound (yield: 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:9]([CH3:15])[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.BrC1SC(C(C2C3C(=C(CSC)C=CC=3)NC=2)CCO)=CN=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:9]([CH3:15])[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Agent: CSCc1cccc2c(C(CCO)c3cnc(Br)s3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3)C(C)CO)c[nH]c12

Procedure:
The title compound was prepared starting from 395 mg (0.98 mmol) of the compound from Example 32A in analogy to the synthesis of the compound from Example 19. 222 mg (63% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([CH2:43][CH3:44])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:45])=[CH:17][C:18]=4[CH2:43][CH3:44])=[N:42][C:27]2=3)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CCc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 7.2 %

Procedure:
A solution of 0.0447 g (0.0712 mmole) 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-201) in 4 mL of dichloromethane was stirred with 2 mL of trifluoroacetic acid for 2 hours and concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.00269 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-piperidin-4-yl-benzamide (I-202) as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[I-:10].[Na+].C(#N)CC.Cl[Si](C)(C)C>[OH-].[Na+]>[I:10][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: [I-]
Reactant: Brc1cnc(Br)c(Br)c1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC#N
Product: Brc1cnc(I)c(Br)c1
Temperature: 105 °C
Reaction time: 0.83 h
Yield: 0.1 %

Procedure:
To a sealed tube was added 2,3,5-tribromopyridine (5.63 g, 17.83 mol), sodium iodide (8.02 g, 53.50 mol), propanenitrile (45 mL), and chlorotrimethylsilane (2.26 mL, 17.83 mol). The resulting mixture was allowed to stir for 50 min at 105° C. The mixture was allowed to cool to rt and 2M NaOH (50 mL) was added. The mixture was extracted with EtOAc (2×80 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-iodo-3,5-dibromopyridine (5.4 g, 83%) as a solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:14]3[CH2:18][NH:17][CH2:16][C@:15]3([CH2:20][OH:21])[CH3:19])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH2:31]([O:38][CH2:39][C:40](Cl)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Li+].[OH-]>C(Cl)Cl.O>[CH2:31]([O:38][CH2:39][C:40]([N:17]1[CH2:18][C@@H:14]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH:7]=2)[C@@:15]([CH2:20][OH:21])([CH3:19])[CH2:16]1)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc([C@@H]2CNC[C@@]2(C)CO)cc1OCC1CC1
Reactant: O=C(Cl)COCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H]2CN(C(=O)COCc3ccccc3)C[C@@]2(C)CO)cc1OCC1CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol (100 mg, 0.34 mmol) was dissolved in CH2Cl2 (1.7 mL), and the solution was cooled to 0° C. DIEA (144 μL, 0.82 mmol) was added, followed by benzyloxyacetyl chloride (114 μL, 0.72 mmol). The reaction was allowed to warm to room temperature slowly and stirred for 18 hours. Water was added (0.25 mL) and the reaction was stirred for 1.5 hours. CH2Cl2 was added and the mixture was washed once with water, twice with iN HCl, once with water, twice with 6% NaHCO3, then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (1 mL) and cooled to 0° C. A solution of LiOH in water (1.36M, 1 mL, 1.36 mmol) was added and the hydrolysis was allowed to proceed at 0° C. for 4 hours. The reaction mixture was quenched with saturated NH4Cl, and the THF was removed by concentrated in vacuo. The residue 6% NaHCO1, dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1.[NH2:13][CH:14]1[CH2:18][S:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1.C1(C2CC(=O)CS2)C=CC=CC=1.C(N(CC)CC)C>O>[CH3:9][O:8][C:7]1[C:2]([NH:13][CH:14]2[CH2:18][S:17][CH:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:15]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:10][O:11][CH3:12]
Reactant: NC1CSC(c2ccccc2)C1
Reactant: COCc1ncnc(Cl)c1OC
Agent: O=C1CSC(c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: O
Product: COCc1ncnc(NC2CSC(c3ccccc3)C2)c1OC
Temperature: 85 °C

Procedure:
1.6 g (8.5 mmol) of 4-chloro-5-methoxy-6-methoxymethylpyrimidine, 1.5 g (8.5 mmol) of 4-amino-2-phenyltetrahydrothiophene (prepared from 2-phenyl-4-oxo-tetrahydrothiophene (cf. D. N. Reinhard, W. P. Trompenaars, I. Geevers, Synthesis 1978, 368) analogously to the route given in Example B) and 2 ml (14 mmol) of triethylamine were heated for 24 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After drying and concentrating, the residue was purified by column chromatography using petroleum ether/ethyl acetate (9:1). This gave 1.18 g (42% of theory) of a pale yellow syrup.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.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>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:26][C:25]([F:28])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(C(F)(F)F)cc3)CC2)C1
Temperature: 120 °C
Yield: 37 %

Procedure:
Sodium t-butylate (6.24 mmol, 3.0 eq.) was added to a stirred mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.08 mmol, 1.0 eq.) and 1-bromo-4-(trifluoromethyl)benzene (2.08 mmol, 1.0 eq.) in toluene (15 ml) and the reaction mixture was degassed with N2. BINAP (0.12 mmol, 0.06 eq.) and Pd(OAc)2 (0.04 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 10% ethyl acetate in hexane), so that the desired product was achieved. Yield: 37%
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C@H:3]1[C:13]([O:15]C(C)(C)C)=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:20][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C@H:3]1[C:13]([OH:15])=[O:14]
Reactant: CC(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Temperature: 120 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A mixture of 1.4 g of the product of Step B, 100 mg of p-toluene sulfonic acid and 14 ml of toluene was stirred at 120° C. for 21/2 hours and was then evaporated to dryness under reduced pressure. The residue was crystallized from isopropyl ether, was cooled and filtered. The product was dried to obtain 900 mg of (1R,cis) 2,2-dimethyl-3-[Z-2-(isopropoxycarbonyl)-ethenyl]-cyclopropane-carboxylic acid melting at 98° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[CH2:17]1[S:22](=[O:24])(=[O:23])[O:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[S:12][CH:13]=[CH:14][N+:15]=2[CH2:20][CH2:19][CH2:18][CH2:17][S:22]([O-:24])(=[O:23])=[O:21])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(N=Nc2nccs2)cc1
Reactant: O=S1(=O)CCCCO1
Solvent: C1CCOC1
Product: CN(C)c1ccc(N=Nc2scc[n+]2CCCCS(=O)(=O)[O-])cc1
Yield: 87 %

Procedure:
8.5 g (36.6 mmol) of N,N-dimethyl-4-[1,3-thiazol-2-yldiazenyl]aniline are heated with 85 ml of butane sultone at 110° C. for 6 hours. After cooling, 200 ml of tetrahydrofuran are added to the reaction mixture and the precipitated product is filtered off, washed with acetone and dried. The dye is recrystallized with methanol/ethyl acetate. 11.8 g (87% of theory) of 4-(2-{[4-(dimethylamino)phenyl]diazenyl}-1,3-thiazol-3-ium-3-yl)-1-butanesulfonate are obtained as a dark blue power.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[CH2:39]O)[CH:32]=[CH:31]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:39][C:37]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:38]=3[N:30]([CH3:29])[CH:31]=[CH:32]4)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc2cccc(CO)c21
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cn1ccc2cccc(COc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)c21

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and (1-methyl-1H-indol-7-yl)-methanol according to the procedure of Example 69. MS (ES) m/z 523.6.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[C:8]([CH3:15])[CH:7]=1.[N+:16]([NH:19][C:20](=[NH:23])SC)([O-:18])=[O:17]>C(O)C>[CH3:13][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:20]([NH:19][N+:16]([O-:18])=[O:17])=[NH:23])=[CH:7][C:8]=1[CH3:15])[CH3:14]
Reactant: Cc1cc(CSCCN)oc1CN(C)C
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CCO
Product: Cc1cc(CSCCNC(=N)N[N+](=O)[O-])oc1CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-[[2-(amino)ethyl]thio]methyl-N,N,3-trimethyl-2-furanmethanamine (1.14 g) and N-nitro-S-methyl-isothiourea (0.65 g) in ethanol (10 ml) was warmed for 5 minutes and stirred for 30 minutes at ambient temperature. The solvent was removed in vacuo and the residue purified by column chromatography (silica/methanol: 0.88 ammonia 100:1). The resulting oil was triturated with petroleum ether (40°-60°) and the solid residue crystallised from toluene yielding the title compound (0.5 g) as a white powder m.p. 84°-85°.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH3:23])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:45]([NH:52][CH2:53][CH:54]([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:45]([N:52]([CH2:53][CH:54]([O:55][CH2:56][CH3:57])[O:58][CH2:59][CH3:60])[C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:23])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(CNCc1ccccc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid 1.98 g (6.0 mmol), a solution of 1-hydroxybenzotriazol 1.01 g (7.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 1.44 g (7.5 mmol) in dichloromethane 20 ml, and a solution of N-benzyl-2,2-diethoxyethanamine (Compound IV-1) 1.12 g (5.0 mmol) and 4-dimethylaminopyridine 61 mg (0.5 mmol) in dichloromethane 5 ml were added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 20 ml and washed with saturated aqueous sodium bicarbonate 20 ml, water 20 ml and brine 20 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 70:30) to obtain the title compound 1.1 g (yield 42%).