Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[C@H:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:19]([NH:29][C@H:30]([C:35](O)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:35](=[O:36])[C@@H:30]([NH:29][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:32][S:33][CH3:34])[C@H:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
(1S,2S,4R)-4-(tert-Butyldimethylsilyloxy)-2-isopropylcyclohexanamine (2.9 g) was dissolved in DMF (36 mL) and cooled to 0° C. prior to the addition of N-Cbz methionine (5.5 g), 4-methyl morpholine (3.8 g), and BOP (8.7 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (S)-1-((1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-isopropylcyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (5.3 g). MS found: (M+H)+=537.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:30]([O:33][CH2:34][C:35]1[C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=[CH:37][C:36]=1[N:50]1[CH2:62][CH2:61][N:53]2[C:54]3[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=3[CH:60]=[C:52]2[C:51]1=[O:63])(=[O:32])[CH3:31].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:30]([O:33][CH2:34][C:35]1[C:36]([N:50]2[CH2:62][CH2:61][N:53]3[C:54]4[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=4[CH:60]=[C:52]3[C:51]2=[O:63])=[CH:37][CH:38]=[CH:39][C:40]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:32])[CH3:31]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 301a (500 mg, 1.077 mmol), 2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 114a (546 mg, 1.292 mmol), Pd(PPh3)4 (62 mg, 0.054 mmol), Na2CO3 aqueous solution (1.0 N, 3.55 mL, 3.55 mmol), 1,2-dimethoxyethane (4.3 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. Methylene chloride (200 mL) was added and the resulting mixture was washed with water (3×30 mL), brine (30 mL), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 301b.
Reaction SMILES: B(Br)(Br)Br.C([O:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)CC.O>ClCCl>[OH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCCCCCc1ccc(-c2ccc(-c3ccc(OCCC)s3)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCCCc1ccc(-c2ccc(-c3ccc(O)s3)cc2)cc1
Reaction time: 8 h

Procedure:
A 1M solution of boron tribromide in dichloromethane (50 cm3) is added dropwise to a solution of 2-propyloxy-5-(4′-hexylbiphenyl-4-yl)thiophene [Zh. Org. Khim., (1979) Vol. 49, pp. 476] (1.0 g) and dichloromethane (50 cm3) at 0° C. under an atmosphere of nitrogen. The reaction solution is stirred overnight and water (100 cm3) added. The organic layer is separated off and the aqueous layer extracted with dichloromethane (2×100 cm3). The combined organic layers are washed with brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue is purified by column chromatography on silica gel using a 9:1 hexane/ethyl acetate mixture as eluent and recrystallisation from ethanol to yield 0.4 g of g 2-hydroxy-5-(4′-hexylbiphenyl-4-yl)thiophene.
Reaction SMILES: C([Li])CCC.[CH:6]1([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[I:16]I.O>O1CCCC1>[CH:6]1([N:11]2[C:15]([I:16])=[N:14][N:13]=[N:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: c1nnnn1C1CCCC1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Ic1nnnn1C1CCCC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
In an atmosphere of inert gas, 10.42 mmol of butyllithium (1.6M in hexane) was added dropwise to a solution, cooled to −75° C., of 8.68 mmol (1.20 g) of 1-cyclopentyltetrazole in 27 ml of anhydrous tetrahydrofuran such that the temperature of the reaction mixture did not exceed −70° C. The mixture was stirred at this temperature for 30 minutes, and 8.68 mmol (2.2 g) of iodine in 4 ml of anhydrous tetrahydrofuran was then added dropwise. After 30 minutes of stirring at this temperature, the reaction mixture was warmed to 23° C., and water was added carefully. The solvent was extracted with ethyl acetate and the combined organic phase was washed with sodium thiosulphate solution and saturated sodium chloride solution and dried over sodium sulphate. The solid obtained after distillative removal of solvent under reduced pressure was stirred with diisopropyl ether and yielded 1.55 g (68%) of 1-cyclopentyl-5-iodotetrazole with a melting point of 119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:33])[CH:12]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:9][O:10][C:11](=[O:33])[CH:12]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:27][CH:26]=1)=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccc(CCl)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccc(COc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
p-Fluorophenol (75 mg, 0.7 mmol) was dissolved in DMSO along with 181 mg (0.5 mmol) 2-(4-chloromethylbenzyloxycarbonyl)amino-3-phenyl-propionic acid methyl ester 37. Cesium carbonate (300 mg) was added, and the suspension was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ether and dilute aqueous HCl. The organic phase was dried, evaporated and chromatographed to give about 121 mg of 2-[4-(4-fluorophenoxy methyl) benzyloxycarbonylamino]-3-phenyl-propionic acid methyl ester 38.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11](C(F)(F)F)=[CH:10][C:9]=1[NH:24][C:25](=[O:45])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH:42]3[CH2:44][CH2:43]3)[CH:36]=2)[CH:30]=1)=O)(C)(C)C.[C:47](O)([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[CH:42]1([C:37]2[CH:36]=[C:35]([C:31]3[CH:30]=[C:29]([C:27]4[CH2:26][C:25](=[O:45])[NH:24][C:9]5[CH:10]=[C:11]([C:49]([F:52])([F:51])[F:50])[C:12]([O:48][CH2:47][C:49]([F:52])([F:51])[F:50])=[CH:13][C:8]=5[N:7]=4)[CH:34]=[CH:33][CH:32]=3)[CH:40]=[C:39]([CH3:41])[N:38]=2)[CH2:43][CH2:44]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C2CC2)n1
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C2CC2)n1

Procedure:
The title compound was prepared from [2-{3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M239) (308 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (199 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:41]([C:40]4[C:35]([CH3:34])=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:42])=[CH:3][C:4]=3[Cl:24])=[O:7])[CH2:9][C:10]=12
Reactant: Cc1ncccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.1 g of 10, 11-dihydro-10-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[2, 1-c][1, 4]benzodiazepine and 3 ml of N,N-diisopropylethylamine in 100 ml of methylene chloride is stirred while a solution of 600 mg of 2-methylpyridine-3-carbonyl chloride in 15 ml of methylene chloride is added slowly. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with water and the organic layer washed with water, dried(MgSO4), filtered and evaporated in vacuo to a residue. The product is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give the desired product as a pale yellow residue. M+ =456.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])=[CH:11][C:10]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:5]=[CH:6][C:7]=1[F:8].BrC1OC([C:35]([N:37]2CC(=O)NC2)=O)=CC=1C1C=CC=C(Cl)C=1>>[Cl:28][C:24]1[CH:23]=[C:22]([C:10]2[CH:11]=[C:12]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])[O:13][C:9]=2[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:35]#[N:37])[CH:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)c(Cl)c3)o2)CN1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(Br)o2)CN1
Product: N#Cc1cc(-c2oc(C(=O)N3CNC(=O)C3)cc2-c2cccc(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 25 starting with the compound from Example 30A. 11.0 mg (20% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15]C)=[O:14])=[C:11]([O:17][CH3:18])[N:10]=[C:9]([S:19][CH3:20])[N:8]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:17][CH3:18])[N:10]=[C:9]([S:19][CH3:20])[N:8]=1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SC)nc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)O)cc1Cl

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-methoxy-2-methylthiopyrimidine (prepared in the above (1)) 271 mg, a 2.0M aqueous sodium hydroxide solution 3.53 ml, water 2 ml and dimethyl sulfoxide 6 ml is stirred at 65° C. for 14 hours. After cooling the reaction mixture is neutralized with a 10% aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo and the resulting powder is triturated with isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-methoxy-2-methylthiopyrimidine as a colorless crystalline powder, 210 mg. mp 167-170° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[N+]=[N-])[CH3:2].[OH:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.N#N.O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH:17]2[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[O:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH3:2]
Reactant: OC1CCOCC1
Reactant: CCOC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CC2)cc1
Agent: N#N
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of compound 2-[4-(Cyclopropanesulfonyl)phenyl]-2-diazo acetic acid ethyl ester (11.3 g, 38 mmol) in DCM (110 mL) under argon atmosphere, 4-hydroxy tetrahydropyran (4.36 mL, 45 mmol) was added followed by portion wise addition of rhodium(II)acetate dimer (0.354 g, 0.8 mmol). Reaction proceeds with evolution of N2 gas. Reaction mixture was stirred at 25° C. for 0.5 h. Completion of reaction was confirmed by TLC and reaction mixture was poured into water (100 mL). Organic layer was separated; aqueous layer was again extracted with of DCM (250 mL). Combined organic layer was washed with water (100 mL) and then with aqueous saturated sodium bicarbonate (300 mL) followed by brine (75 mL). Organic layer was dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with DCM (100 mL) and solvent was evaporated under reduced pressure using rotavapour to get required crude product. The crude product was purified by column chromatography using silica gel 100-200 mesh, mobile phase hexanes to 35% ethyl acetate in hexanes. Removal of solvent from appropriate fractions under reduced pressure in rotavapour gave pure product.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].C([Si]([O:20][C:21]1[CH:26]=[C:25]([F:27])[C:24](B2OC(C)(C)C(C)(C)O2)=[C:23]([F:37])[CH:22]=1)(C)C)(C)(C)C>>[F:27][C:25]1[CH:26]=[C:21]([OH:20])[CH:22]=[C:23]([F:37])[C:24]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC1(C)OB(c2c(F)cc(O[Si](C)(C)C(C)(C)C)cc2F)OC1(C)C
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(O)cc2F)n1
Yield: 65 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and tert-butyl(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (1.75 equiv.) to give methyl 6-(2,6-difluoro-4-hydroxyphenyl)-5-fluoropicolinate in 65% yield. The reaction was heated for an additional 30 minutes at 100° C. in the microwave to drive to completion the deprotection of the TBDMS group. LC/MS=283.9 (M+H), Rt=0.69 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:13]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(Br)C(F)(F)C(F)(F)F
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)C(F)(F)F
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A mixture of 3,5-dichlorophenylboronic acid (793 mg, 4.15 mmol), 2-bromo-3,3,4,4,4-pentafluorobut-1-ene (1.0 g, 4.57 mmol), K2CO3 (1.14 g, 8.3 mmol) and Pd(PPh3)2Cl2 (58 mg, 0.08 mmol) in THF (4 mL) and H2O (2 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to give the crude desired product (800 mg; 66% yield) as colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]([F:30])([F:29])[CH2:26]CI>C(#N)C>[F:24][C:25]([F:30])([F:29])[CH2:26][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1
Reactant: Oc1c(C2CCNCC2)cccc1C(F)(F)F
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Oc1c(C2CCN(CC(F)(F)F)CC2)cccc1C(F)(F)F

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethyl)phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1,1,1-trifluoro-3-iodopropane (0.01 ml). MS m/z (relative intensity, 70 eV) 341 (M+, 40), 258 (bp), 195 (25), 167 (28), 152 (56).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=4)[CH:18]([CH3:22])[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:33]1[CH:37]=[N:36][N:35]=[C:34]1[NH2:38]>>[S:33]1[CH:37]=[N:36][N:35]=[C:34]1[NH:38][C:19](=[O:20])[CH:18]([CH3:22])[CH:17]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=1)[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2
Reactant: COC(=O)c1ccc(C(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)C(=O)O)cc1
Reactant: Nc1nncs1
Product: COC(=O)c1ccc(C(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)C(=O)Nc2nncs2)cc1
Yield: 25 %

Procedure:
Example 153 was prepared from 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-(4-(methoxycarbonyl)phenyl)-2-methylpropanoic acid and 1,3,4-thiadiazol-2-amine using General Coupling Method A to give 35 mg (25% yield, 3 steps). MS found: (M+H)+=516.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CCCO)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CCCBr)cc1Cl
Yield: 91.8 %

Procedure:
Compound 55-2 (2.34 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.66 g) and N-bromosuccinimide (2.48 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.88 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(O)(C(F)(F)F)=[O:12].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:12])=[C:4]([F:10])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: NC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Yield: 87.4 %

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in a 70 mL mixture of TFA (56.0 mL, 727 mmol)-sulfuric acid (14.0 mL, 263 mmol) (4:1 VAT) was stirred at 40° C. for 16 h. The reaction was poured while still warm over ice water. The product precipitated and the solid was filtered and dried to give 4-bromo-2-fluorobenzamide (9.53 g, 43.7 mmol, 87% yield) as a white solid. MS (ESI) m/z 218.1 [M]+, 220.1 [M+2]+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[Cl:6][CH2:7][C:8]([NH2:10])=[O:9]>>[Cl:6][CH2:7][C:8]([NH:10][CH:2]([OH:3])[C:1]([OH:5])=[O:4])=[O:9]
Reactant: O=CC(=O)O
Reactant: NC(=O)CCl
Product: O=C(CCl)NC(O)C(=O)O
Temperature: 50 °C
Yield: 56.7 %

Procedure:
740 g of an aqueous solution with 50% of glyoxylic acid (5 moles) are mixed with 514 g of chloracetamide (5.5 moles). The mixture is heated to 50° C, then the greater part of the water is removed under vacuum, 1200 g of acetic acid are added and it is cooled on ice. After filtration and drying, 475 g of product are obtained. The product concentrated under vacuum gives 112 g of a second crop, namely a total yield of 69%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:13][CH2:12]1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 5-fluoro-3-(piperidin-4-yl)-1H-indole (0.87 g, 4.0 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.76 g, 4.0 mmol). The product was isolated as a white foam. Yield 1.14 g (70%). mp 94°-97° C. FDMS m/e=407 (M+ of free base). α[D]589 =+8.36 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: [CH2:1]([S:8][C:9]1([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])([CH3:19])[CH3:18]>>[CH2:1]([S:8][C:9]1([CH2:15][NH:16][C:30]([NH:29][C:21]2[C:20]([CH:17]([CH3:18])[CH3:19])=[CH:25][CH:24]=[CH:23][C:22]=2[CH:26]([CH3:28])[CH3:27])=[O:31])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NCC1(SCc2ccccc2)CCCCC1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(SCc2ccccc2)CCCCC1
Yield: 45.1 %

Procedure:
Similarly to Example 1(c), by reaction of 120 mg (0.51 mmol) of C-(1-benzylsulfanyl-cyclohexyl)-methylamine with 125 μl (0.61 mmol) of 2,6-diisopropylphenylisocyanate. 101 mg of 1-(1-benzylsulfanyl-cyclohexylmethyl)-3-(2,6-diisopropyl-phenyl)-urea is obtained in the form of a white solid. (m.p.=156° C., Yields 45%).