Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](Cl)=[O:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](N)=[CH:13][C:12]=1[O:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].C([N:26](CC)CC)C.O>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:5]2[C:6]([C:7]([NH2:26])=[O:8])=[C:2]([CH3:1])[O:3][CH:4]=2)=[CH:13][C:12]=1[O:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22]
Reactant: CC(C)=CCOc1cc(N)ccc1Cl
Reactant: CCN(CC)CC
Reactant: Cc1occc1C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)=CCOc1cc(-c2coc(C)c2C(N)=O)ccc1Cl
Temperature: 25 °C

Procedure:
A first solution of 2-methyl-3-furancarboxylic chloride (13.57 g) in methylene chloride (94 mL) was stirred in an ice/salt bath. A second solution of 4-chloro-3-(3-methyl-2-butenyloxy)benzenamine (19.8 g), triethylamine (14 mL) in methylene chloride (94 mL) was added to the first solution at such a rate that the temperature was maintained at −5° C. to 0° C. When the addition was complete, the resultant reaction mixture was stirred to ambient temperature and left stirring for 15 hours. Water was added to the reaction mixture and then the organic layer separated and washed successively with water, dilute hydrochloric acid, water, aqueous sodium bicarbonate, and water. After drying (MgSO4), the solvent was removed from the washed organic layer and the residue was recrystallised from isopropyl alcohol to give N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl-2-methyl-3-furancarboxamide, a white solid, 17 g. A second crop of beige crystals, 7.6 g, was also obtained.
Reaction SMILES: N.C1N2CN3CN(C2)C[N:3]1C3.Br[CH:13]([F:35])[C:14]([NH:16][C:17]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])=O)=[O:15].NC1C=CC([N+]([O-])=O)=CC=1C(C1C=CC=CC=1F)=O.BrC(F)C(Br)=O>C(O)C>[F:35][CH:13]1[N:3]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]2[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=[CH:31][C:17]=2[NH:16][C:14]1=[O:15]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(c1ccccc1F)c1cc([N+](=O)[O-])ccc1NC(=O)C(F)Br
Agent: N
Agent: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Agent: O=C(Br)C(F)Br
Solvent: CCO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2F)=NC1F

Procedure:
NH3 is passed into a refluxing solution of 1.48 g. of hexamethylenetetramine in 30 ml. of ethanol; 3.83 g. of 2-(α-bromo-α-fluoroacetamido)-5-nitro-2'-fluorobenzophenone, obtainable from 2-amino-5-nitro-2'-fluorobenzophenone and α-bromo-α-fluoroacetyl bromide, are added over 2 hours. The mixture is then heated under reflux for 3 hours more and is evaporated. The resulting 2-(α-amino-α-fluoroacetamido)-5-nitro-2'-fluorobenzophenone is treated with 15 ml. of toluene and 20 mg. of p-tolunesulfonic acid and is heated under reflux for 1 hour. Working up in the customary manner gives 3-fluoro-5-o-fluorophenyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [C:1]1(/[C:7](/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26]Br)=[CH:20][CH:19]=2)=[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][NH2:29]>C(O)C>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:29][CH3:28])=[CH:20][CH:19]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Reactant: CN
Solvent: CCO
Product: CNCCOc1ccc(C(=C(CCO)c2ccccc2)c2ccccc2)cc1
Yield: 73 %

Procedure:
42.3 g of (Z)-1,2-diphenyl-1-[4-(2-bromoethoxy)phenyl]-1-buten-4-ol is stirred over 500 ml of 33% methylamine in ethanol for 10 h at 100° C. in autoclave. The solvent is evaporated and the evaporation residue is dissolved in ethyl acetate in the presence of 2 M sodium carbonate solution. After washing the ethyl acetate layer with water and drying with sodium sulfate the solvent is evaporated. Recrystallization from toluene gives 27.2 g (73%) of the product having m.p. 134°-9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C([N:13](CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:8][CH:9]=1)[NH:7][N:13]=[CH:10]2
Reactant: CCN(CC)CC
Reactant: COc1ccc(N)c(C)c1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-methoxy-2-methylaniline (2 ml) in dichloromethane (10 ml) was treated with triethylamine (3.27 ml). The mixture was cooled to 0° C. then treated with acetic anhydride (2.38 ml), then stirred at ambient temperature for 1 hour, then cooled to 0° C. when a pink solid precipitated. This solid was filtered, then washed with cold dichloromethane and then dissolved in acetic acid (55 ml) and concentrated hydrochloric acid (20 ml). This solution was cooled to −5° C., then treated with a solution of sodium nitrite (2.68 g) in water (20 ml), then stirred at that temperature for 1 hour and then treated with water (100 ml). This mixture was stirred vigorously at 0° C. for 10 minutes after which a yellow solid precipitated. This solid was filtered, then washed with water and then dissolved in toluene (13 ml). This solution was heated to 80° C. for 1.5 hours, then cooled and then washed with aqueous 1N sodium carbonate solution. The organic phase was extracted three times with aqueous 2N hydrochloric acid and the acid extracts chilled and then made alkaline by addition of aqueous 5N sodium hydroxide solution. The aqueous layers were extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate and then evaporated to yield 5-methoxy-1H-indazole (0.410 g) as a yellow solid. LC-MS (METHOD B): RT=1.32 minutes; 149 (M+H)+. (b) 4-Fluoro-1H-indazole
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:27])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2SC)=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(OC(C1SC(N)=C([C:45]#[N:46])C=1C1C=CC(I)=CC=1)=O)C.C(C1C=CC=CC=1B(O)O)#N>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:27])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:45]#[N:46])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(I)cc1
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(-c2ccccc2SC)cc1
Agent: N#Cc1ccccc1B(O)O
Product: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1

Procedure:
Using a method substantially in accordance with the method of 5-amino-4-cyano-3-(2′methylsulfanyl-biphenyl-4-yl)-thiophene-2-carboxylic acid ethyl ester starting with the compound 5-amino-4-cyano-3(4-iodo-phenyl)-thiophene-2-carboxylic acid ethyl ester and 2-(cyano)phenylboronic acid gives the title compound: 1H NMR (400 MHz, CDCl3) δ 7.81-7.44 (m, 8H), 5.29 (s, 2H), 4.16 (q, 2H, J=7.2 Hz), 1.17 (t, 3H, J=7.3 Hz), MS found (M−1) 372.0 and (M+1)+NH3 391.0.
Reaction SMILES: Cl.[O:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].CCO>CS(C)=O>[Cl:10][CH2:11][C:12]([NH:9][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:13]
Reactant: NOc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCO
Product: O=C(CCl)NOc1ccccc1
Yield: 67 %

Procedure:
This compound was prepared from phenoxyamine hydrochloride and chloroacetyl chloride by the method described in Preparation 1, m.p. 126°-128° (decomp.), λmax (EtOH) 266.5 nm (ε15,400), νmax (Nujol) 3340, 3260, 3140 (--NH--), 1720, 1710, 1690 cm-1 (--CONH--), τ(DMSO d6) 5.79 (ClCH2CO--), -2.2 (--NH--), 2.3-3.2 (phenyl). Yield 67%
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:19][S:20]([CH3:23])(=[O:22])=[O:21].[OH-].[K+]>O>[CH3:5][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:8])[C:10]([CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:11]1
Reactant: CS(=O)(=O)Cc1cnc2ccccc2c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(CS(C)(=O)=O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dimethyl sulphate (3.0 ml.) was added to a stirred solution of 4-hydroxy-3-methylsulphonylmethylquinoline (1.9 g.) and potassium hydroxide (1.4 g.) in water (20 ml.) at 5°. The mixture was stirred at room temperature for 4 hours, then filtered to give the novel 1-methyl-3-methylsulphonylmethyl-4-quinolone, m.p. 204°-205° (from acetone).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10].[Cl-:21].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[C:2]([Cl:21])[CH:3]=2)=[O:17])=[CH:19][CH:20]=1)([O-:11])=[O:10].[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][C:3]=2[Cl:21])=[O:17])=[CH:19][CH:20]=1)([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: [Cl-]
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)c(Cl)c1
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1Cl

Procedure:
A mixture of anisole (8.67 g., 0.08 mole), 4-nitrobenzoyl chloride (16.4 g., 0.088 mole) and methylene chloride (80 ml). at 5° was stirred vigorously and treated with finely powdered aluminum chloride (11.2 g., 0.084 mole). The reaction mixture was stirred at room temperature for 20 hrs. and then decomposed with ice and hydrochloric acid (15 ml.). The aqueous solution was extracted twice with methylene chloride. The combined methylene chloride solution was washed with aqueous sodium bicarbonate solution and finally with water. The organic layer was dried (MgSO4) and filtered. The solvent was removed in vacuo, and the residue on triturating with methanol gave the product, m.p. 121°-122°. This product was used in the next step without purification. 4-(4-nitrobenzoyl)-2-chloroanisole and 4-(4-nitrobenzoyl)-3-chloroanisole were prepared by the same procedure.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-])=O)[N:6]=1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc2c(N)cccc2n1

Procedure:
400 mg (1.7 mmol) of 2-acetylamino-5-nitroquinoline and 105 mg of 10% Pd—C are stirred in 20 ml of ethyl acetate-MeOH (3:1) for 4 hours in a hydrogen atmosphere at room temperature. The batch is filtered, concentrated by evaporation and purified by column chromatography on silica gel with hexane-ethyl acetate: 210 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22](S(C)(=O)=O)[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[C-:36]#[N:37].[Na+].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22]([C:36]#[N:37])[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)c1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 6.6 %

Procedure:
To a solution of the compound obtained in Example 33 (300 mg) in dimethylformamide (10 mL) was added sodium cyanide (42.1 mg) and the mixture was stirred at 10° C. for 1.5 hours in a microwave reactor. After cooling to room temperature, to the reaction mixture was added ethyl acetate and an aqueous sodium hydrogencarbonate solution and the mixture was stirred. The organic layer was washed with water and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80/20 to 65/35) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-cyano-3-(N-cyclopentylcarbamoyl)pyrazolo[1,5-a]pyrimidine (17.8 mg; yield: 81%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][OH:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:15]([OH:34])(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl.C(N=C=N[CH2:41][CH2:42][CH2:43]N(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:15]([O:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][O:14][C:15](=[O:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])(=[O:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:43][CH2:42][CH3:41]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N(CCO)CCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
tert-Butyl bis(2-hydroxyethyl)carbamate (Aldrich; 600 mg, 2.92 mmol) was dissolved in dichloromethane (30 mL), and stirred overnight at room temperature after adding oleic acid (Tokyo Chemical Industry Co., Ltd.; 1.82 g, 6.43 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.29 g, 6.72 mmol), and 4-dimethylaminopyridine (89 mg, 0.731 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (hexane/chloroform=50/50 to 0/100) to give tert-butyl N,N-bis(2-((Z)-octadec-9-enoyloxy)ethyl)carbamate (1.26 g, 58.7%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH:21]([NH2:28])[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH:21]([NH:28][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CC(N)c2cccnc2)cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC(NC(=O)c2ccccc2)c2cccnc2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
9.75 g of benzoyl chloride in 10 ml of chloroform are added, cooling in ice, to 14.9 g of 2-(3,4-dimethoxyphenyl)-1-(3-pyridyl)ethylamine and 12.1 g of triethylamine in 200 ml of chloroform. The mixture is stirred at room temperature for 4 hours, the chloroform is distilled out in vacuo and the residue is washed with toluene and water. 18.5 g of the amide of melting point 156°-158° C. are obtained.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].CC(C)=O.[ClH:27]>C(O)C.O>[ClH:27].[O:14]([CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CCCN(CCOc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above ester (3.5 g, 13 mmol) was dissolved in ethanol (35 ml) and 4N sodium hydroxide (3.2 ml) was added. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and 4M hydrochloric acid (6.3 ml) was added. The mixture was concentrated in vacuo and dichloromethane (50 ml) and acetone were added to the residue. The mixture was concentrated in vacuo to give a solid residue which was heated at reflux with acetone (500 ml). The mixture was filtered while still hot and the filtrate was left overnight for crystallisation. The solid which formed was isolated by filtration and dried to give 1.0 g of the title compound as a solid.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].Cl[Si](C)(C)C.CN1CCOCC1.Cl[CH2:25][CH2:26][O:27][C:28](Cl)=[O:29].[C:31]([OH:35])(=[O:34])[CH2:32][CH3:33]>ClCCl>[C:31]([O:35][CH:26]([O:27][C:28]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:29])[CH3:25])(=[O:34])[CH2:32][CH3:33]
Reactant: O=C(Cl)OCCCl
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCC(=O)O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general procedure for the one pot synthesis, tranexamic acid (786 mg, 5.0 mmol) was reacted with chlorotrimethylsilane (1.396 mL, 1.195 g, 11.0 mmol) in anhydrous dichloromethane (10 mL) and in the presence of N-methylmorpholine (1.374 mL, 1.264 g, 12.5 mmol). Subsequent reaction of the intermediate with chloroethylchloroformate (0.82 mL, 1.07 g, 7.5 mmol) followed by a mixture of NMM (2.75 mL, 2.53 g, 25 mmol) and propionic acid (3.73 mL, 3.70 g, 50 mmol) yielded the title compound 9 (103 mg, 7% yield) as colorless, very viscous oil after aqueous work-up and two mass-guided preparative HPLC purifications. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 2H), 1.03 (t, J=7.6 Hz, 3H), 1.17-1.35 (br. m, 3H), 1.38 (d, J=5.2 Hz, 3H), 1.65-1.73 (br. m, 2H), 1.83-1.91 (br. m, 2H), 2.09 (tt, J=12.4, 3.6 Hz, 1H), 2.26-2.33 (m, 2H), 2.74-2.90 (m, 2H), 6.64 (q, J=5.6 Hz, 1H), 7.44 (t, J=5.6 Hz, 1H), 11.99 (br. s, 1H). MS (ESI) m/z 324.14 (M+Na)+; 300.10 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]([CH2:13][CH3:14])[CH:9]([C:11]#[N:12])[OH:10])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][OH:18]>CO.C[O-].[Na+]>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:9]([OH:10])[C:11](=[NH:12])[NH:17][OH:18])[CH2:13][CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: NO
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)C(=N)NO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 32.2 %

Procedure:
A solution of (2-cyano-1-ethyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester (9.53 g, 44 mmol) in methanol (80 ml) was cooled to 0° C. and treated successively with hydroxylamine hydrochloride (3.05 g, 44 mmol) in methanol (80 ml) and 25% sodium methoxide solution in methanol (10.2 ml). After stirring at 0° C. for 5 minutes the reaction mixture stirred at room temperature for 5 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and then evaporated under reduced pressure. The residual yellow oil was subjected to mplc, eluting with a mixture of ethyl acetate and heptane to give {(S)-1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (3.5 g) as white solid. MS: M(H+) 248.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1>C(OC)(OC)(OC)C>[OH:10][C:9]1[N:11]=[C:12]([CH3:13])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)NNc1ccccc1
Agent: COC(C)(OC)OC
Product: Cc1nc(O)nn1-c1ccccc1
Reaction time: 5 h

Procedure:
Twenty-five g of 1-phenylsemicarbazide and 150 ml of trimethyl orthoacetate were combined, and 100 mg of p-toluenesulfonic acid was added. The mixture was stirred on a steam bath for 5 hours, and was then cooled and evaporated under vacuum. The residue was recrystallized from ethanol to obtain 24.6 g of the desired product.
Reaction SMILES: [Cl:1][O-].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[NH:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=1[C:14]#[N:15].C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:1][C:12]1[C:13]([C:14]#[N:15])=[C:9]([C:5]2[S:4][CH:8]=[CH:7][CH:6]=2)[NH:10][C:11]=1[C:16]([F:19])([F:17])[F:18]
Reactant: [O-]Cl
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1cccs1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(-c2cccs2)[nH]c(C(F)(F)F)c1Cl
Reaction time: 0.25 h
Yield: 15 %

Procedure:
Sodium hypochlorite (12 mL of a 5.25% solution, 17 mmol) is added dropwise to a solution of 2-(2-thienyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (2.00 g, 8.26 mmol) in tetrahydrofuran. The reaction mixture is stirred for 2 hours and 15 minutes, quenched with a 1% sodium bisulfite solution and diluted with ether. The layers are separated and the organic layer is washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to obtain a yellow solid. Flash chromatography of the solid using silica gel and a 15% ethyl acetate in hexane solution gives a solid which is recrystallized from ethyl acetate and hexane to obtain the title product as a yellow solid (0.35 g, 15%, mp 221°-223° C.).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1)=[O:28].[CH2:38]([NH:41][CH3:42])[CH:39]=[CH2:40]>>[F:37][C:32]1[CH:31]=[C:30]([O:29][C:27](=[O:28])[N:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:41]([CH2:38][CH:39]=[CH2:40])[CH3:42])[CH2:7][CH2:8]2)[CH3:1])[CH:35]=[C:34]([F:36])[CH:33]=1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: O=C(Cl)Oc1cc(F)cc(F)c1
Reactant: C=CCNC
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C)CCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2cc(F)cc(F)c2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 3,5-difluoro-phenyl chloroformate were reacted, followed by treatment with N-allyl-N-methylamine to give trans-{4-[5-(Allyl-methyl-amino)-pentyl]-cyclohexyl}-methyl-carbamic acid 3,5-difluoro-phenyl ester, MS: 409 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][C:9]=2[F:17])=[C:4]([F:18])[CH:3]=1.[Mg].[CH2:20]([CH:25]1[CH2:30][CH2:29][SiH:28](OC)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1>[CH2:20]([C@H:25]1[CH2:26][CH2:27][Si@H:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][C:9]=3[F:17])=[C:4]([F:18])[CH:3]=2)[CH2:29][CH2:30]1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCc1ccc(-c2ccc(Br)cc2F)c(F)c1
Reactant: CCCCCC1CC[SiH](OC)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[Si@H](c2ccc(-c3ccc(CCC)cc3F)c(F)c2)CC1

Procedure:
6.2 g (20 mmol) of 4-bromo-2,2'-difluoro-4'-propylbiphenyl was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 4.0 g (20 mmol) of 4-n-pentyl-1-methoxy-1-silacyclohexane to obtain 4'-(trans-4-n-pentyl-1-silacyclohexyl)-2,2'-difluoro-4-propylbiphenyl. The silacyclohexane rings of this product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 6.4 g of the trans isomers (yield 80%).