Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([O-:26])=[O:25])=[O:3].[Na+].C[Si](C)(C)Cl.[SiH3]NC(=O)C(F)(F)F.[C:41]1([CH2:47][C:48](Cl)=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:41]1([CH2:47][C:48]([CH:16]([C:17]2[S:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:13][CH:10]2[C:11](=[O:12])[N:8]3[C:7]([C:24]([OH:26])=[O:25])=[C:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[CH2:23][S:22][C@H:9]23)=[O:15])=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: O=C(Cl)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C(N[SiH3])C(F)(F)F
Agent: [Na+]
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)Cc3ccccc3)c3cccs3)[C@H]2SC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium cephalothin (3.36 g.) in anhydrous alcohol-free chloroform (20 ml.) is silylated by the addition of trimethylchlorosilane (2.2 ml.). After stirring for 30 minutes, monosilyltrifluoroacetamide (5.0 ml.) and phenylacetyl chloride (4.0 ml.) are added and the mixture is then heated to 45° C. for two days under a condenser fitted with a drying tube. The volatiles are evaporated to afford a residue which is dissolved in 100 ml. of ethyl acetate and washed three times with water. The ethyl acetate layer is dried over magnesium sulfate, filtered and the solution evaporated in vacuo to a residue. The residue is triturated with chloroform, any insolubles are removed by filtration and the product precipitated from the filtrate with hexane. This procedure is followed two more times. The 7-(phenylacetyl-2-thienylacetyl)amino-3-acetoxymethyl-3-cephem-4-carboxylic acid is obtained in a solvent-free form by freeze drying from a solution in benzene.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)([OH:18])[C:14]([F:16])([F:17])[F:15])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:10]
Reactant: O=C(O)c1cccs1
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1.[Br:24][CH2:25][C:26](Br)=O.C([O-])(=O)C.[Na+]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]2[N:11]3[C:26]([CH2:25][Br:24])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[CH:18][CH:19]=3)[C:6]=2[CH:22]=1
Reactant: O=C(Br)CBr
Reactant: CSc1ccc(C2=NCC(NN)=Nc3c(C)cc(C)cc32)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CSc1ccc(C2=NCc3nnc(CBr)n3-c3c(C)cc(C)cc32)cc1

Procedure:
In the manner given in Preparation 2, 7,9-dimethyl-5-[p-(methylthio)phenyl]-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with bromoacetyl bromide and after 1.5 hours with sodium acetate, than the mixture was refluxed to give 8,10-dimethyl-1-(bromomethyl)-6-[p-(methylthio)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[F:10][C:11]([F:16])([F:15])[CH2:12][CH2:13]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:13][CH2:12][C:11]([F:16])([F:15])[F:10])=[CH:6][N:7]=1
Reactant: OCCC(F)(F)F
Reactant: Cc1cc(Cl)ncc1O
Product: Cc1cc(Cl)ncc1OCCC(F)(F)F
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (3.64 g, a pale yellow solid) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and 3,3,3-trifluoropropan-1-ol (5.72 g, 50.1 mmol) in a similar manner to Step-1 of Intermediate-A17.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[OH:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].N1C=CC=CC=1>ClCCl>[C:8]([O:12][C:6]([NH:5][S:2]([O:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])(=[O:4])=[O:3])=[O:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)O
Reactant: O=C1CCC(=O)N1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To chlorosulfonylisocyanate (10.3 g) was added t-butyl alcohol (6.96 ml) in dichloromethane (30 ml) under ice-water cooling and the mixture was stirred at ambient temperature for 0.5 hour. The solution was added into a mixture of N-hydroxysuccinimide (8.38 g) and pyridine (6.47 ml) in dichloromethane (150 ml) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The solution was washed with 0.1N hydrochloric acid, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (200:1, 100:1, 200:3, 50:1) to give N-(t-butoxycarbonylamino-sulfonyloxy)succinimide as colorless oil (2.93 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH2:14][OH:15])[CH:10]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1
Reactant: OCc1c[nH]c(-c2c(F)cccc2F)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1c[nH]c(-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution (26 mL) of [5-(2,6-difluorophenyl)-1H-pyrrol-3-yl]methanol (2.56 g) in acetonitrile were added tetra-n-propylammonium perruthenate (430 mg), N-methylmorpholine N-oxide (2.15 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (60 mL) and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as pale-red crystals (yield 1.94 g, 77%).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[S:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][N:31]=1>>[S:32]([C:29]1[S:28][C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:31][CH:30]=1)(=[O:34])(=[O:33])[NH2:35]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ncc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1cnc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-thiazole-5-sulfonic acid amide [CAS-No. 63735-95-5] according to general procedure II. Light yellow solid. MS (ISP) 517.2 [(M−H)−]; mp 311° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([C@@](O)([C@@H](O)[C@H](O)[C@H](O)CO)C(N)=O)=[CH:16][CH:15]=1.ClC(OC1C=CC([N+:43]([O-])=O)=CC=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[C:18]([NH2:43])[CH:17]=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc([C@](O)(C(N)=O)[C@@H](O)[C@H](O)[C@H](O)CO)cc2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1

Procedure:
1.54 g (5.0 mmol) of enantiomer B of intermediate 1 were reacted with 1.1 equivalents of 4-nitrophenyl chloroformate in a similar manner to the method described in Example 6, intermediate 1 to obtain 1.87 g of the title compound.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.Cl.[CH:13]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([S:26]([C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31])(=[O:28])=[O:27])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:15][CH2:14]1>ClCCl>[CH:13]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([S:26]([C:29]([CH3:33])([CH3:34])[C:30]([NH:4][CH2:3][CH2:1][OH:2])=[O:31])(=[O:28])=[O:27])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:14][CH2:15]1
Reactant: NCCO
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)Cl)ccc2n1CC1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)NCCO)ccc2n1CC1CC1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a mixture of ethanolamine (54 mg, 0.886 mmol), triethylamine (0.184 mL, 1.32 mmol) and dichloromethane (3 mL) was added a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoyl chloride hydrochloride (Step A of Example 7, 198 mg, 0.443 mmol) in dichloromethane (2 mL) at room temperature. After stirring at the same temperature for 1 h, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (ODS, gradient elution with acetonitrile/0.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (105 mg, 55%) as an amorphous.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([NH:18][NH2:19])=[O:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=O)[C:24]=2[CH:23]=[CH:22][N:21]=1.C(O)(=O)C>C(O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:15][CH:14]3[C:16]([NH:18]/[N:19]=[CH:30]/[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH:23]=[CH:22][N:21]=[CH:20]4)=[O:17])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NNC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Reactant: O=Cc1cccc2cnccc12
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(N/N=C/c1cccc2cnccc12)C1CC1c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a room temperature solution of 2-(4-cyclohexylphenyl)cyclopropanecarbohydrazide (200 mg) in ethanol (20 mL), was added isoquinoline-5-carbaldehyde (122 mg, 0.77 mmol) and acetic acid (0.5 mL). The reaction mixture was then heated at 80° C. for 3 h, concentrated in vacuo and the residue diluted with water and extracted with EtOAc (2×20 mL). The layers were separated and then the combined organic layers were washed with a saturated NaHCO3 solution, dried over magnesium sulfate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via column chromatography eluting with 2% MeOH in dichloromethane to afford (E)-2-(4-cyclohexylphenyl)-N′-(isoquinolin-5-ylmethylene)cyclopropanecarbohydrazide (100 mg, 33%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1O.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](=[O:23])([O-])[O-].[K+].[K+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:23][CH2:20][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH2:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
3,4-Dihydroxy-1-nitrobenzene was benzylated by refluxing with benzyl bromide with potassium carbonate as a base in acetone which on reduction with sodium dithionite gave 3,4-dibenzyloxy aniline. This was coupled to 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid using N,N-1,3-diisopropylcarbodiimide in the presence of 1-hydroxybenzotriazole to provide the amide. The amide was then debenzylated by hydrogenation in presence of palladium on carbon.
Reaction SMILES: C([Mg]Cl)C.I[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[O:30]=[C:31]1[CH2:40][CH2:39][CH2:38][C:37]2[CH:36]=[C:35]([C:41]#[N:42])[CH:34]=[CH:33][C:32]1=2>ClCCl>[OH:30][C:31]1([C:6]2[N:7]=[CH:8][N:9]([C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]=2)[CH2:40][CH2:39][CH2:38][C:37]2[CH:36]=[C:35]([C:41]#[N:42])[CH:34]=[CH:33][C:32]1=2
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Cl
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCCC2(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.75 h

Procedure:
12 mmol of ethylmagnesium chloride (3M in diethyl ether) are added to a solution of 10 mmol of 4-iodo-1-trityl-1H-imidazole [96797-15-8] in 40 ml of dichloromethane. The mixture is stirred for 45 minutes, and a solution of 10 mmol of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [90401-84-6] in 15 ml of dichloromethane is added. The reaction mixture is stirred at room temperature overnight and quenched with saturated ammonium chloride solution. The phases are separated, and the aqueous phase is extracted with dichloromethane (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.O.O.O.O.O.[OH-].C[N+](C)(C)C.Br[CH2:34][CH2:35][OH:36].Cl>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:34][CH2:35][OH:36])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Temperature: 50 °C
Yield: 95.7 %

Procedure:
To 4-(6-chloro-2,3-dihydro-indol-1-yl)-quinazolin-7-ol (125 mg, 0.42 mmol; from Example 65) in DMF (2 mL) was added H2O (50 μL), K2 CO3 (s) (116 mg, 0.84 mmol), and tetramethylammonium hydroxide pentahydrate (15 mg, 0.08 mmol) followed by 2-bromoethanol (39 μL, 0.46 mmol). The mixture was stirred at 50° C. under N2(g) and aliquots of 2-bromoethanol (3×20 μL) were added at 24 hour invervals. Extractive workup and chromatography analogous to that described in Example 1 followed by conversion to the HCl salt as outlined for Example 2 afforded 76 mg (53%) of product. (M.P. 215°-217° C.; LC-MS: 342 (MH+); anal. RP18-HPLC RT: 4.09 min.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][CH2:14][C:15](=O)[CH2:16][CH3:17].N1CCCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:14]([C:15]1([CH2:16][CH3:17])[CH2:2][C:1](=[O:3])[C:4]2[CH:5]=[C:6]([C:7]#[N:8])[CH:9]=[CH:10][C:11]=2[O:12]1)[CH3:13]
Reactant: CC(=O)c1cc(C#N)ccc1O
Reactant: CCC(=O)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCC1(CC)CC(=O)c2cc(C#N)ccc2O1
Reaction time: 3.5 h

Procedure:
To a suspension of 3-acetyl-4-hydroxybenzonitrile (10.48 g) and 3-pentanone (10.3 ml) in toluene (20 ml) was added pyrrolidine (2.7 ml) at ambient temperature. The reaction mixture was stirred overnight at the same temperature and for 3.5 hours under reflux, diluted with ethyl acetate, and then washed with water, 10% aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine successively. The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified with silica gel column chromatography using a mixture of methylene chloride and n-hexane (1:10→1:1) as an eluent. The fractions containing the object compound were concentrated in vacuo and the residue was triturated to give 2,2-diethyl-3,4-dihydro-4-oxo-2H-1-benzopyran-6-carbonitrile (2.51 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH:12]1[C:19](=[O:20])[CH:18]2[CH:14]([CH2:15][C:16](=O)[CH2:17]2)[C:13]1=[O:22])[CH3:2].[C:23](#[N:27])[CH2:24][C:25]#[N:26].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH:12]1[C:19](=[O:20])[CH:18]2[CH:14]([CH2:15][C:16](=[C:24]([C:23]#[N:27])[C:25]#[N:26])[CH2:17]2)[C:13]1=[O:22])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(=O)CC2C1=O
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(=C(C#N)C#N)CC2C1=O

Procedure:
0.500 g (1.70 mmol) of 2-(2,6-diethyl-4-methylphenyl)tetrahydropentalene-1,3,5-trione (example I-a-4 from WO 2010/040460), 250 mg of malononitrile, 150 mg of ammonium acetate and 0.3 ml of glacial acetic acid in 30 ml of toluene are heated at reflux for 2 h. After cooling, the solvent is distilled off and the mixture is taken up in ethyl acetate, washed twice with water, then dried (magnesium sulphate) and concentrated on a rotary evaporator. What remains is a yellow oil which is chromatographed on silica gel using ethyl acetate/hexane 1:6. This gives 0.32 g (56%) of a colourless oil.
Reaction SMILES: C([O:5][C:6](=[O:46])[C@H:7]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:8][C:9](=[O:38])[CH2:10][N:11]([C:17](=[O:37])[C@H:18]([CH3:36])[NH:19][C@@H:20]([C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.CC(C)=O.CCOCC.[ClH:56]>C(OCC)(=O)C>[ClH:56].[CH2:32]([O:31][C:29]([C@H:20]([NH:19][C@H:18]([C:17]([N:11]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:46])=[O:5])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:38])=[O:37])[CH3:36])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:30])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)C1CCCC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)O)C1CCCC1

Procedure:
N-[1(R)-Butoxycarbonyl-3-phenylpropyl]-L-alanyl-N-cyclopentylglycyl-L-phenylalanine tert-butyl ester (1 g) is dissolved in 14 ml of 3.4N hydrogen chloride in ethyl acetate, followed by addition of 2 ml of acetone. Then, 10 ml of ether is added and the solvent is decanted off. The residue is dried under reduced pressure to give 0.8 g of N-[1(R)-butoxycarbonyl-3-phenylpropyl]-L-alanyl-N-cyclopentylglycyl-L-phenylalanine hydrochloride as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][NH:7][C:8](=[O:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=1.Cl.O1CCOCC1.Cl>C(O)(C)C>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[N:20][C:15]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[CH2:6][NH:7][C:8](=[O:11])[NH:9][CH2:10][C:4]=3[CH:3]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)CNC(=O)NC2
Reactant: CS(=O)(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccccc1Nc1nc(Nc2ccc3c(c2)CNC(=O)NC3)ncc1Cl
Yield: 1 %

Procedure:
A solution of 7-amino-1,2,4,5-tetrahydro-(2,4)-benzodiazepin-3-one (75.0 mg, 0.42 mmol) in isopropanol (3 mL) was treated with N-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide (140.2 mg, 0.42 mmol) and 4N HCl/Dioxane (0.106 mL, 0.50 mmol). The reaction mixture was irradiated at 130° C. for a total of 60 minutes. The reaction mixture was then reduced en vacuo and the product was purified and isolated flash column chromatography (0% MeOH/DCM-15% MeOH/DCM) to afford 1.98 mg of N-{2-[5-Chloro-2-(3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,3]diazepin-7-ylamino)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide as the HCl salt. The compound was isolated as a foam, LC/MS (ESI)=480.35 (M+H). 1H NMR (400 MHz, MeOD, d4) δ 7.68 (m, 2H), 7.46 (m, 1H), 7.29 (m, 2H), 7.06 (m, 4H), 6.62 (m, 1H), 4.31 (m, 2H), 4.19 (m, 2H), 3.47 (s, 1H), 3.12 (s, 1H), 2.92 (s, 3H).
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[C:13]([F:14])=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:10]=[CH:11][C:12]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[C:13]([F:14])[C:8]=2[F:7])=[CH:19][CH:20]=1)[CH3:25]
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2F)cc1
Reactant: Brc1ccc[se]1
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: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2F)cc1

Procedure:
A mixture of 56.0 g (0.27 mol) of 2-bromoselenophene, 70.0 g (0.27 mol) of 2,3-difluoro-4′-ethylbiphenyl-4-ylboronic acid, 22.0 g (19.0 mmol) of tetrakis(triphenylphosphine)palladium(0) and 800 ml of 2 N sodium carbonate soln. in 2.5 l of toluene/ethanol (1:1) is heated at 90° C. for 17 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with water, and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-(4′-Ethyl-2,3-difluorobiphenyl-4-yl)-selenophene is obtained as a yellowish solid.
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[C:12]([O:20][CH:21]([O:23][C:24]([NH:26][CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1)=[O:25])[CH3:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+:41].C(#N)C>O>[C:12]([O:20][CH:21]([O:23][C:24]([NH:26][CH2:27][C@H:28]1[CH2:29][CH2:30][C@H:31]([C:34]([O-:36])=[O:35])[CH2:32][CH2:33]1)=[O:25])[CH3:22])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[Na+:41]
Reactant: CC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)c1ccccc1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1)OC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 2.096 g (6.0 mmol) of trans-4-{[1-(benzoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid 23 was reacted with 504.1 mg (6.0 mmol) of sodium bicarbonate (NaHCO3) in 20 mL of a mixture of acetonitrile and water (1:1) to yield 2.23 g (quant.) of the title compound 24 as a colorless powder. 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.86 (m, 2H), 1.08-1.21 (m, 2H), 1.22-1.32 (m, 1H), 1.53 (d, J=5.6 Hz, 3H), 1.59-1.84 (br. m, 5H), 2.73-2.86 (m, 2H), 6.88 (q, J=5.6 Hz, 1H), 7.47-7.56 (m, 3H), 7.64-7.70 (m, 1H), 7.89-7.94 (m, 2H). MS (ESI) m/z 372.10 (M+Na)+; 348.12 (M−H)−.