Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C(OCC)(=O)C.C1CCCCC1.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>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 4 g (10.75 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 3.3. of Example 3, 5.50 g (28.96 mmol) of 4-(trifluoromethyl)-phenylboronic acid, 9.12 g (42.99 mmol) of hydrated potassium phosphate and 1.24 g (1.07 mmol) of tetrakis(triphenylphosphine)palladium, and after chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane, 2.78 g of product are obtained in the form of a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:10]([O:20]C)=[N:11][C:12]([CH3:19])=[CH:13][C:14]=1[O:15][CH:16]([F:18])[F:17])(C)(C)C>Cl>[NH2:7][CH2:8][C:9]1[C:10](=[O:20])[NH:11][C:12]([CH3:19])=[CH:13][C:14]=1[O:15][CH:16]([F:17])[F:18]
Reactant: COc1nc(C)cc(OC(F)F)c1CNC(=O)OC(C)(C)C
Agent: Cl
Product: Cc1cc(OC(F)F)c(CN)c(=O)[nH]1
Yield: 80.7 %

Procedure:
To a solution of tert-butyl((4-(difluoromethoxy)-2-methoxy-6-methylpyridin-3-yl)methyl)carbamate (830 mg, 2.61 mmol) in HCl (10 mL) was stirred at 100° C. for 1.5 hours under N2. The mixture was concentrated to afford 3-(aminomethyl)-4-(difluoromethoxy)-6-methylpyridin-2(1H)-one (430 mg, yellow solid, 80.8% yield). LCMS (M+H+) m/z: calcd 204.07. found 205.0. 1H NMR (400 MHz, DMSO): δ 7.621-7.258 (t, 1H), 6.26 (s, 1H), 3.837-3.822 (d, J=6.0 Hz,2H)
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:12]=[CH:13][CH:14]=2.[N:15]1([CH:20]([CH3:24])[CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][N:17]=[CH:16]1>O1CCOCC1>[Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:23][CH2:22][CH2:21][CH:20]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH3:24])[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: CC(CCN)n1ccnc1
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Solvent: C1COCCO1
Product: CC(CCNC1=Nc2ccc(Br)c3cccc1c23)n1ccnc1
Yield: 41.3 %

Procedure:
A mixture of 5.2 g of 6-bromo-benz[cd]indole-2-thiol, 2.8 g of 3-(1H-imidazol-1-yl)butanamine, 6.6 g of mercuric acetate and 100 ml of dry p-dioxane was reacted as described in Example 1, giving 3.0 g of the desired product, mp 240°-241° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:18].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: O=C(O)c1c(O)cccc1F
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1c(O)cccc1F
Temperature: 0 °C
Reaction time: 20 h
Yield: 51.5 %

Procedure:
2-Fluoro-6-hydoxybenzoic acid (20.0 g, 0.128 mol) and oxalyl chloride (22.3 ml, 0.256 mol) were dissolved in ethyl acetate (300 ml) together with N,N-dimethylformamide (DMF) (2 drops) and the mixture was stirred under an atmosphere of nitrogen for 20 h. The solvent was removed by distillation under reduced pressure leaving the crude acid chloride which was redissolved in ethyl acetate (300 ml) and cooled to 0° C. Concentrated aqueous ammonia (d 0.88, 50 ml) was added dropwise and the mixture was stirred for a further 2 h. The mixture was poured into aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×200 ml). The combined organic phases were dried (MgSO4) and concentrated leaving the crude compound (10.2 g, 51.5%). Mass spectrum (-ve CI)m /z 154 (M+ -H) .
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:54])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][C@@H:28]1[C@@H:32]([CH2:33][O:34][Si](C(C)(C)C)(C)C)[CH2:31][N:30]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=2[O:51][CH3:52])[C:29]1=[O:53]>C1COCC1>[CH3:19][O:20][C:21](=[O:54])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][C@@H:28]1[C@@H:32]([CH2:33][OH:34])[CH2:31][N:30]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=2[O:51][CH3:52])[C:29]1=[O:53]
Reactant: COC(=O)CCCC#CC[C@H]1C(=O)N(Cc2ccc(OC)cc2OC)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)CCCC#CC[C@H]1C(=O)N(Cc2ccc(OC)cc2OC)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 4.0 mL, 4.0 mmol) was added to a solution of 7-[(3R*,4R*)-4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-2-oxo-pyrrolidin-3-yl]-hept-5-ynoic acid methyl ester (680 mg, 1.31 mmol) in THF (13 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature. After 18 h at room temperature, THF was removed in vacuo and the residue was taken up in EtOAc (50 mL). The organic phase was washed with water (2×20 mL) and brine (20 mL) then dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (85% EtOAc/hexane→EtOAc, gradient) to afford 304 mg (57%) of 7-[(3R*,4R*)-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxo-pyrrolidin-3-yl]-hept-5-ynoic acid methyl ester.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17]O)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:17][C:5]1[C:6]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Temperature: 5 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 30 g (105.58 mmol) of [5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-yl]-methanol in 210 mL of dichloromethane is added 41.96 g (158 mmol) of triphenylphosphine. The resulting mixture is cooled in an ice bath (about 0-10° C.) and added in portions to carbon tetrabromide (53 g, 158.37 mmol). The reaction is stirred at room temperature for 2 h. The Solvent is evaporated to obtain an orange oil which is purified on silica gel column chromatography using Hexanes to hex/EtOAc 8:2 as eluent, to obtain 33 g of the title compound as a white solid (90%). MS (m/e): 346 (M+1).
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][C:13]2([O:20][CH2:19][CH2:18][O:17]2)[C@@:12]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH:24]=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC>[CH2:3]([O:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][C:13]2([O:17][CH2:18][CH2:19][O:20]2)[C@@:12]1([CH3:26])[CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [Li]C
Reactant: C[C@]1(CCCC=O)[C@H](OCc2ccccc2)CCCC12OCCO2
Solvent: CCOCC
Product: CC(O)CCC[C@@]1(C)[C@H](OCc2ccccc2)CCCC12OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Methyllithium (63.3 ml, 0.0918 l mol, 1.45 M in ether) is added dropwise to a solution of the aldehyde, (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-cyclohexane (25.4 g, 0.0765 mol) in ether (1000 ) at 0° C. in a nitrogen atmosphere. The cooling bath is removed and the mixture is stirred for 0.5 hours at ambient temperature. The mixture is then poured into a cold saturated sodium chloride solution (500 ml). The ether phase is separated and the aqueous phase is extracted with ether (3×100 ml). The ether phases are combined, dried (MgSO4) and the solvent is removed at reduced pressure. The crude product (27.1 g) is chromatographed on SilicAR CC-7 (300 g, Mallinckrodt) in hexane. Elution with 10% ethyl acetate/hexane gives (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane as a colorless oil (25.8 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]([OH:30])=[O:29]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: Cc1cc(C=Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(CCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Reaction time: 6 h
Yield: 109.7 %

Procedure:
A suspension of [(2-methyl-4-{2-[4′-(trifluoromethyl)-3-biphenylyl]ethenyl}phenyl)oxy]acetic acid (90 mg, 0.22 mmol) in EtOH (10 mL) was added to Pd/C (Degussa type E101 NE/N) (10 mg, 11 wt %) and the resulting mixture stirred under an atmosphere of hydrogen for 6 hours. The mixture was then filtered through celite J2 washing with copious amounts of EtOH and the filtrate reduced under vacuum to give a sticky solid (100 mg) which was purified by mass directed auto-prep HPLC to give the title compound as a fluffy white solid (25 mg).
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][S:8]([C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])(=[O:10])=[O:9])=[O:5])C.[NH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][NH:24][C:12]([C:11]([S:8]([CH2:7][CH:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:4]([OH:5])=[O:3])(=[O:10])=[O:9])([CH3:16])[CH3:15])=[O:13]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)O
Reactant: NCCOCCO
Product: CC(C)(C(=O)NCCOCCO)S(=O)(=O)CC(Cc1ccccc1)C(=O)O

Procedure:
In an analogous manner to that described in Example 6, paragraphs (a) to (c), starting from 2-mercaptoisobutyric acid and ethyl 2-benzylacrylate there was obtained (RS)-2-[[2-[(ethoxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionic acid, reaction of which 2-(2-aminoethoxy)ethanol and subsequent enzymatic hydrolysis of the resulting ethyl ester yielded (S/R=9/1 )-α-[[[1-[[2-(2-hydroxyethoxy)ethyl]carbamoyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamic acid, MS: 401.9 (M+H)+, as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][NH2:16])(=[O:12])=[O:11])([O-:3])=[O:2].[OH:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20](O)=[O:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)Cl>[OH:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]([NH:16][CH2:15][CH2:14][NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[O:17]
Reactant: NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(CO)C(=O)NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-(2-nitrobenzenesulfonyl)ethylenediamine, 3-hydroxy-2,2-dimethylpropionic acid, EDCI, HOBt, methylene chloride, and DMF was stirred at ambient temperature for 4 hours to yield 3-hydroxy-2,2-dimethyl-N-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)propanamide. A mixture of this compound, triphenylphosphine, a toluene solution of diethyl azodicarboxylate, and THF was stirred at 0° C. for 15 hours to yield 6,6-dimethyl-1-[(2-nitrophenyl)sulfonyl]-1,4-diazepan-5-one. A mixture of this compound, 4-methylbenzenethiol, potassium carbonate, and acetonitrile was stirred at ambient temperature for 3 hours to yield 6,6-dimethyl-1,4-diazepan-5-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:4]=1
Reactant: O=C=Nc1cc([N+](=O)[O-])ccc1F
Reactant: C1CCNC1
Solvent: ClCCl
Product: Nc1ccc(F)c(NC(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-fluoro-2-isocyanato-4-nitrobenzene (1.125 g, 6.18 mmoles) and pyrrolidine (485 mg, 6.8 mmoles) in DCM (20 mL) was stirred at r.t. for 14 hrs. After concentrated, the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous citric acid solution and dried over MgSO4, followed by hydrogenation with Pd/C (wet, 10%, 0.15 g) under a hydrogen balloon overnight. After filtration and concentration, the reasonable pure N-(5-amino-2-fluorophenyl)pyrrolidine-1-carboxamide (3, 1.44 g) was used for the next reactions. MS+: 224.2, UV: λ=271.6 nm. 1H NMR: (DMSO) δ7.44 (s, 1H), δ6.78 (m, 1H), δ6.20 (m, 1H), δ3.32 (m, 4H), δ1.83 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[H-].[Na+].Br[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1.O>CN(C)C=O>[CH:26]([C:23]1[CH:22]=[CH:21][C:20](/[CH:19]=[CH:18]/[CH2:17][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:25][CH:24]=1)([CH3:28])[CH3:27]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(C)c1ccc(/C=C/CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OC/C=C/c2ccc(C(C)C)cc2)c(C)c(C)c1NC=O
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
To a solution of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (5.20 g, 29.0 mmol) in N,N-dimethylformamide (30 ml) was added at 0° C. under a nitrogen atmosphere sodium hydride (a 60% dispersion in liquid paraffin, 1.39 g, 34.8 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added 1-[(E)-3-bromo-1-propenyl]-4-isopropylbenzene (9.00 g, 37.7 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate-hexane to obtain 5.80 g (59% yield) of the title compound. Melting point: 165-167° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NC3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 4-aminotetrahydropyran and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f27) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: I/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)#[CH:19]>>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[CH:2][C:19]#[C:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:6]=1
Reactant: Cc1ccc(-c2cc(C)ccc2/C=C/I)cc1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Product: Cc1ccc(-c2cc(C)ccc2C=CC#Cc2ccc(C(=O)O)cc2)cc1
Yield: 28.4 %

Procedure:
In a similar manner to that of Example 1(e), by reaction of 3.69 g (11.0 mmol) of 2-((E)-2-iodovinyl)-5,4'-dimethylbiphenyl obtained in Example 13(f) with 1.60 g (10.0 mmol) of methyl 4-ethynylbenzoate, 1.00 g (27%) of the expected compound is obtained in the form of a white powder with a melting point of 123-125° C.
Reaction SMILES: BrC1C=C[C:5]2[N:6]([CH2:16]CCCCC)[C:7]3[C:12]([C:13]=2C=1)=CC(Br)=CC=3.[Br:22][C:23]1[CH:41]=[CH:40][C:26]([N:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>>[CH3:16][N:6]1[CH:7]=[CH:12][CH:13]=[C:5]1[C:37]1[CH:36]=[C:35]2[C:34](=[CH:39][CH:38]=1)[N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:26]1[CH:25]=[CH:24][C:23]([Br:22])=[CH:41][C:40]2=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCn1c2ccc(Br)cc2c2cc(Br)ccc21
Product: CCCCCCn1c2ccc(Br)cc2c2cc(-c3cccn3C)ccc21

Procedure:
The compound of the present example was synthesized by the same method as described in example 1, except that 4.09 parts of 3,6-dibromo-9-hexyl-9H-carbazole (31) was used to substitute 4-bromo-N,N-diphenyl aniline.
Reaction SMILES: [N+:1]([C:4]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:5][OH:6])([O-:3])=[O:2].[F:11][S:12]([F:19])=[C:13](O)[C:14]([F:17])([F:16])[F:15]>>[F:11][S:12]([F:19])=[C:13]([O:6][CH2:5][C:4]([N+:8]([O-:10])=[O:9])([N+:1]([O-:3])=[O:2])[CH3:7])[C:14]([F:17])([F:16])[F:15]
Reactant: CC(CO)([N+](=O)[O-])[N+](=O)[O-]
Reactant: OC(=S(F)F)C(F)(F)F
Product: CC(COC(=S(F)F)C(F)(F)F)([N+](=O)[O-])[N+](=O)[O-]
Yield: 95 %

Procedure:
Using a method similar to example 12, 2,2-dinitropropanol and pentafluorothioacetic acid were reacted to form 2,2-dinitropropyl pentafluorothioacetate (95% yield) mp 22° C.;
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.C([O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=1[O:35][CH3:36])C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:33][C:31]4[CH:30]=[CH:29][C:28]([O:35][CH3:36])=[C:27]([CH:32]=4)[C:26]([OH:37])=[O:25])[CH2:21][CH2:22]3)=[CH:7][N:8]2[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)cn(Cc3cccs3)c2c1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: COc1ccc(CN2CCC(c3cn(Cc4cccs4)c4cc(F)ccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.9 g (9.2 mmol) of 6-fluoro-3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole and 2.7 g (11.5 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard work-up, 1.2 g (27% of yield) of the expected acid were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=1.[H-].[Na+].[C:17]([Si:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]I)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].O>CN(C=O)C>[C:17]([Si:21]([CH3:22])([CH3:23])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][N:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]1=[O:14])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=c1nc(-c2ccccc2F)cc[nH]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCn1ccc(-c2ccccc2F)nc1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1H-pyrimidin-2-one (375 mg, 1.97 mmol) in dry DMF (50 ml), 60% NaH (103 mg, 2.56 mmol) was added portionwise. After heating the mixture at 100° C. for 1 hour, tert-butyl-(4-iodo-butoxy)-dimethyl-silane (664 μl 2.56 mmol) was added at room temperature and the mixture was stirred overnight. Water was added and the mixture extracted with diethyl ether; the organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography with petroleum ether-ethyl acetate (1-1) to give 370 mg of the title compound as a yellow solid (50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH2:23][CH3:24])[C:17]=2[CH:25]=1)=[O:12].[CH3:26]I>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH2:23][CH3:24])[C:17]=2[CH:25]=1)=[O:12]
Reactant: CCN1C(=O)COc2ccc(C(=O)Cc3ccc(OC)cc3Cl)cc21
Reactant: CI
Product: CCN1C(=O)COc2ccc(C(=O)C(C)c3ccc(OC)cc3Cl)cc21

Procedure:
In analogy to Example 56, step 2, 6-[2-(2-chloro-4-methoxy-phenyl)-acetyl]-4-ethyl-4H-benzo[1,4]oxazin-3-one (7.7 g) was reacted with methyl iodide at r.t. for 5.5 h. The product was purified by column chromatography (silica gel, heptane/AcOEt 2:1) to give the title compound (5.1 g) as a white solid. MS (m/e)=374.1 [M+H+]
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (310 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow oil (280 mg, 52%).