Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:11]1[CH2:15][CH:14]([CH3:16])[CH:13]([C:17]2[N:21]3[C:22]4[CH:28]=[CH:27][NH:26][C:23]=4[N:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:36][Si:37]([CH2:40][CH2:41][O:42][CH2:43]Cl)([CH3:39])[CH3:38]>CN(C=O)C>[CH2:29]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:11]1[CH2:12][CH:13]([C:17]2[N:21]3[C:22]4[CH:28]=[CH:27][N:26]([CH2:43][O:42][CH2:41][CH2:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:23]=4[N:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]([CH3:16])[CH2:15]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1c1cnc2cnc3[nH]ccc3n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.3 %

Procedure:
To the suspension of sodium hydride (60% dispersion in mineral oil, 0.382 g, 9.55 mmol) in DMF (50 mL) was added a solution of N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine (3.96 g, 9.09 mmol) in DMF (50 mL) drop-wise at about 0° C. The resulting solution was stirred at ambient temperature for about 10 min. SEM chloride (1.774 mL, 10.0 mmol) was added drop-wise and the solution was stirred for about 1 h. The solvent was removed under reduced pressure and the residue was partitioned between water and EtOAc (200 mL each). The organic layer was washed with brine (100 mL), dried over anhydrous MgSO4, filtered and concd. The residue was purified by silica gel column chromatography eluting with 10-80% EtOAc in DCM to yield N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (3.1 g, 60% yield) as an off-white amorphous solid. LC/MS (Table 1, Method a) Rt=3.32 min; MS m/z 566 (M+H)+.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(CC)C1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)C1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 43b (1.1 g, 2.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.2 g, 98%).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][N:6]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:5]=1.O>CCO>[NH2:3][C:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:5]=1
Reactant: CCOC(=O)c1cn(-c2ncccn2)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nn(-c2ncccn2)cc1C(=O)O
Temperature: 50 °C

Procedure:
A 1 N aqueous sodium hydroxide solution (3.0 mL) is added to a suspension of ethyl 3-amino-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylate (500 mg, 2.14 mmol) in 6.0 mL of EtOH. The reaction mixture is heated to 50° C. for 16 h. After cooling to RT, water is added, and the mixture is extracted with EtOAc (3×20 mL). The aqueous layer is cooled to 0° C. and acidified to pH=2 with conc. HCl. The precipitated solid is collected by vacuum filtration and dried in vacuo to give the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: CCCn1c(=O)cc(N)n(C)c1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(=O)c(N=O)c(N)n(C)c1=O
Temperature: 10 °C
Yield: 535.8 %

Procedure:
6-Amino-1-methyl-3-n-propyluracil (13.2 g, 7.3 mmol) was dissolved in 10-15 ml of acetic acid and the solution was warmed on a hot plate to 60°-70° C. Then, with stirring, a solution of sodium nitrite (5.3 g, 7.7 mmol) in 100 ml of water was added in 10 ml portions over 10 minutes. A brownish-purple precipitate formed. The reaction mixture was cooled to 10° C. and the precipitate was collected by vacuum filtration, washed with 10 ml of acetone, and air-dried to give 8.3 g (55%) of 6-amino-1-methyl-5-nitroso-3-n-propyluracil as a purple solid. 1H NMR (DMSO-d6 +D2O) δ0.90 (t, J=7 Hz, 3 H), 1.62 (sextet, J=7 Hz, 2 H), 3.26 (s, 3 H), 3.87 (t, J=7 Hz, 2 H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[I:1])[NH:11]2)=[CH:16][CH:15]=1)=[O:25]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COc1nccc(I)c1-c1cc2ccc(N)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1nccc(I)c1-c1cc2ccc(NC(=O)c3cccc(Cl)c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of 2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (50 mg, 0.14 mmol) in CH2Cl2 (5 mL) was added 3-chlorobenzoic acid (21 mg, 0.14 mmol) and HATU (52 mg, 0.14 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 3-chloro-N-[2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-benzamide (56 mg, 81%) as a white solid. MH+ 503.8.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:17]=3)[CH:12](O)[CH2:11][C:10]=2[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CCN(S(F)(F)[F:36])CC>ClCCl>[F:36][CH:12]1[CH2:11][C:10]2[CH:9]=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][C:15]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:17]=2
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCCCOc1ccc2c(c1)CC(O)c1cc(OCCCCCC)ccc1-2
Solvent: ClCCl
Product: CCCCCCOc1ccc2c(c1)CC(F)c1cc(OCCCCCC)ccc1-2

Procedure:
From 2,7-dihexyloxy-9,10-dihydrophenanthren-9-ol by reaction with DAST in abs. dichloromethane.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)([CH3:14])[CH3:13])=[CH:6][CH:5]=1.I([O-])(=O)(=O)=[O:25].[Na+].Cl>CO.CCOCC>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:11][C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)([CH3:13])[CH3:14])=[O:25])=[CH:6][CH:5]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(CSc1ccc(Cl)cc1)NCCCn1ccnc1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(CS(=O)c1ccc(Cl)cc1)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-[2-(4-Chlorophenylthio)-1,1-dimethylethyl]-3-(imidazol-1-yl)propylamine dihydrochloride (1.0 g) was added in one portion to a stirred solution of sodium periodate (0.54 g) in aqueous methanol (15 ml of a 1:1 mixture) at 5-10° C. The mixture was stirred at ambient temperature for 24 hours and then evaporated to dryness. 5M Sodium hydroxide solution was added to the residue and the mixture extracted with dichloromethane to give an oil which was dissolved in ether containing a small amount of absolute alcohol and treated with ethereal hydrogen chloride. The mixture was filtered to give N-[2-(4-chlorophenylsulphinyl)-1,1-dimethylethyl]-3-(imidazol-1-yl)propylamine dihydrochloride, m.p. 208-211° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].S(=O)(=O)(O)O.[S-:17][C:18]#[N:19].[Na+].C1OCCOCCOCCOCCOC1>ClC1C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:18]([NH2:19])=[S:17]
Reactant: COC(=O)c1cccc(N)c1
Reactant: N#C[S-]
Agent: C1COCCOCCOCCOCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc(NC(N)=S)c1
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
11.3 g of methyl 3-aminobenzoate are initially introduced into the reaction vessel as a solution in 75 ml of chlorobenzene, 2.07 ml of concentrated sulfuric acid (96%) are added dropwise at −5 to 0° C. in the course of 15 minutes, stirring is continued for 5 minutes, 6.8 g of sodium thiocyanate are then introduced in portions at a maximum of 0° C. and the mixture is stirred for a further 15 minutes. 0.2 ml of 15-crown-5 is then added, the mixture is stirred at a bath temperature of 100° C. for 10 hours and cooled and the precipitate formed is filtered off and washed 3 times with water. 13.5 g (85.9%) of the title compound of melting point 171-172° C. result.
Reaction SMILES: C1COCC1.[BH4-].[Na+].CS(O)(=O)=O.[O:13]=[C:14]([N:28]1[CH2:33][CH2:32][N:31]2[C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=[C:30]2[CH2:29]1)[CH:15]=[C:16]([NH2:27])[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26]>CC(O)C>[O:13]=[C:14]([N:28]1[CH2:33][CH2:32][N:31]2[C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=[C:30]2[CH2:29]1)[CH2:15][CH:16]([NH2:27])[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CS(=O)(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reaction time: 5 h

Procedure:
In a 250 mL round bottom flask THF (110 mL) was taken. It was cooled to less than −5° C. and NaBH4 (2.81 g) was added. After that methanesulfonic acid (17.8 g) was added dropwise at less than −5° C. over a period of 1 h. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (10.0 g) is mixed in a solvent mixture of THF (25 mL) and IPA (11 mL) and added into the reaction mixture, keeping the temperature below 0° C. It was stirred for 4-6 h below 5° C. After usual work-up procedure, product was extracted in a suitable solvent. Extract was washed and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-9.5 g, % Y-94.5%, % Purity by HPLC-94.6%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[CH2:11][NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([S:27](=[O:30])(=[O:29])[NH2:28])=[C:20]([CH3:31])[C:16]=1[C:17](Cl)=[O:18]>CC(CC)=O>[CH:1]1([N:6]2[CH2:10][CH2:9][CH2:8][CH:7]2[CH2:11][NH:12][C:17](=[O:18])[C:16]2[C:20]([CH3:31])=[C:21]([S:27](=[O:30])(=[O:29])[NH2:28])[CH:22]=[C:23]([CH:24]([CH3:26])[CH3:25])[C:15]=2[O:14][CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)Cl
Reactant: NCC1CCCN1C1CCCC1
Solvent: CCC(C)=O
Product: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)NCC1CCCN1C1CCCC1
Yield: 16.5 %

Procedure:
3.4 g of 1-cyclopentyl-2-aminomethylpyrrolidine (0.020 mole) and 40 ml of methyl-ethyl-ketone are placed in a 250 flask fitted with an agitator, a thermometer and a dropping funnel. The mixture is cooled to about +10° C., then a solution of 5.5 g of 2-methoxy-3-isopropyl-5-sulphamoyl-6-methylbenzoyl chloride (0.018 mole) in 40 ml of methyl-ethyl-ketone is poured in drop by drop. The mixture is reacted 1 hour at room temperature, then the solvent is evaporated under vacuum and the residue dissolved in 100 ml of hydrochloric acid (density 1.18). An insoluble rubbery product is filtered off, and the filtrate is made alkaline with 15 ml of ammonia (density 0.91). The precipitate formed is filtered, washed with water then re-crystallised in 30 ml of ethyl acetate. The crystals are filtered, washed with a little solvent and dried in an oven at 50°046732772 C. 1.3 g (17%) of product is obtained, melting at 196° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=2)[NH:13][C:12]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(#N)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:18]=2)[NH:13][C:12]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1[nH]c2ccc(OCCCBr)cc2c1C(=O)OCc1ccccc1
Solvent: CC#N
Product: Cc1[nH]c2ccc(OCCCN3CCCC3)cc2c1C(=O)OCc1ccccc1
Yield: 42.1 %

Procedure:
5-(3-Bromo-propoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.244 g, 0.605 mmol, 1 eq) was suspended in dry acetonitrile (10 mL) under Ar. Pyrrolidine (0.100 mL, 1.210 mmol, 2 eq) was added. The reaction mixture was stirred and heated to reflux for 24 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.100 g (42%) of the indole-pyrrolidine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 393 (M+1); Anal. Calcd for C24H28N2O3.HCl.H2O: C, 64.49; H, 6.99; N, 6.27; Found: C, 64.36; H, 6.93; N, 6.15.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Cl-].[Cl-].[Cl-].[Al+3].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:4][CH:3]([CH3:5])[CH2:2][C:1]([C:15]1[CH:16]=[CH:17][C:12]([CH3:18])=[CH:13][CH:14]=1)=[O:6]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Add slowly isovaleryl chloride (3.0 g, 24.88 mmol) to an ice-cold stirred solution of aluminum trichloride (4.976 g, 37.32 mmol) in anhydrous toluene (60 mL). Stir the reaction mixture at ambient temperature overnight. Add slowly ice-cold water and extract the mixture twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the desired intermediate (4.38 g, 100%) that was used without any further purification. GC-MS m/z: 176 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14]C(=O)C=CC1C=CC=CC=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[C:25](=[O:28])([O-])[O-].[K+].[K+]>CC(CC)=O>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]([CH2:2][C:25](=[O:28])[CH:2]=[CH:1][C:4]1[CH:5]=[CH:6][CH:11]=[CH:12][CH:13]=1)=[O:3]
Reactant: COC(=O)c1ccc(OC(=O)C=Cc2ccccc2)c(C(C)=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(O)c(C(=O)CC(=O)C=Cc2ccccc2)c1
Yield: 135.1 %

Procedure:
Methyl 3-acetyl-4-cinnamoyloxy-benzoate (46.2 g; m.p. 97°-99° C) was dissolved in methyl-ethyl-ketone (350 ml). After addition of anhydrous potassium carbonate (37 g), the mixture was refluxed for 6 hours. After cooling, dilution with petroleum ether (500 ml) and filtration, the collected precipitate was dissolved in water, acidified with acetic acid, extracted with ethylacetate. The organic phase was washed with potassium carbonate 5% and water, then evaporated to dryness. After crystallisation from methanol, (2-hydroxy-5-carbomethoxy-benzoyl)-cinnamoyl-methane (31.2 g; m.p. 138°-140° C) was obtained, which was refluxed for 15 minutes with formic acid 99% (140 ml). After cooling, dilution with water (l. 1) and filtration, the collected precipitate was crystallised from acetone to obtain 6-carbomethoxy-2-(β-phenyl-vinyl)-chromone (27.8 g; m.p. 175°-177° C) which was hydrolysed with a solution of potassium hydroxide 1% (600 ml) in ethanol 95% at reflux temperature for 45 minutes. After cooling, acidification with acetic acid, concentration under vacuum and dilution with water, the precipitate was collected and washed with water to give, after crystallisation from acetone, 6-carboxy-2-(β-phenyl-vinyl)-chromone (16.1 g; m.p. 273°-275° C).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]([C:40]1[N:41]=[C:42]([NH:45][C:46]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[S:43][CH:44]=1)[C:10]([NH:12][CH:13]1[C:38](=[O:39])[N:15]2[C:16]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:17]([CH2:20][Cl:21])[CH2:18][S:19][C@H:14]12)=[O:11].ClC1C=CC=C(C(OO)=[O:73])C=1.O>C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]([C:40]1[N:41]=[C:42]([NH:45][C:46]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[S:43][CH:44]=1)[C:10]([NH:12][CH:13]1[C:38](=[O:39])[N:15]2[C:16]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:17]([CH2:20][Cl:21])[CH2:18][S:19](=[O:73])[C@H:14]12)=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h
Yield: 104.3 %

Procedure:
To a solution of benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (6.5 g) in ethyl acetate (40 ml) was added dropwise a solution of m-chloroperbenzoic acid (1.54 g) in ethyl acetate (10 ml) at 0° C. The mixture was stirred for two hours under ice-cooling and then poured into a mixture of ethyl acetate (50 ml) and water (100 ml). The organic layer was washed with brine and then dried. The solvent was evaporated in vacuo and the residue was pulverized with diisopropyl ether to give benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (6.90 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[CH3:21]I.[OH-].[Na+]>CC(N(C)C)=O.C1COCC1>[C:2]([O:5][C:6]([N:8]([CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]1)[CH3:21])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 20 g (77.7 mmol) of BOC-tranexamic acid in 162 mL of DMA and 320 mL of THF was cooled to 0° C. and treated with 7.46 g (170.99 mmol, 2.2 eq) of NaH (55% in oil) over 30 min. The mixture was warmed to RT, cooled to 0° C. again and treated with 77.42 mL (1243 mmol, 16 eq) of CH3I and warmed to RT overnight. 230 mL (2487.1 mmol, 32 eq) of aqueous 32% NaOH were added at 0° C., the solution was stirred for 1 h at RT and partitioned between Et2O (×3)/H2O. The organic phase was evaporated to remove the DMA. The residue was dissolved in 100 mL of dioxane and treated with 233 mL (233 mmol) of aqueous 1M NaOH at RT, and the solution was stirred overnight. The reaction was partitioned between Et2O (×3)/H2O, the aqueous phase was acidified with aqueous 10% KHSO4 and partitioned between Et2O (×3), washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 19.2 g (87%) of trans-4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexane-carboxylic acid, MS: 270 (M−H−).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH3:7])[C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[Si:21]([O:1][C@H:2]1[CH2:6][N:5]([CH3:7])[C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C
Reaction time: 12 h

Procedure:
Methyl (2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate 3b (6 g, 37 mmol) was dissolved in 100 mL of dichloromethane, followed by addition of imidazole (7.70 g, 113 mmol) and tert-butyl dimethylchlorosilane (6.80 g, 45 mmol) successively. After stirring for 12 hours, the reaction mixture was diluted with 100 mL of dichloromethane, washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound methyl (2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidine-2-carboxylate 3c crude product as a colourless oil, which was directly used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 53.3 %

Procedure:
Under ice-cooling, a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (1 g, 6.51 mmol) in THF (40 mL), was treated with NaH (60% in mineral oil; 438 mg, 10.95 mmol) and the mixture was stirred for 1 h. Trityl chloride (2.17 g, 7.81 mmol) was added and the mixture was stirred at the same temperature for 1 h and further stirred at room temperature for 3 h. The mixture was quenched with saturated NH4Cl and then extracted with EtOAc. The organic layer was washed with water, brine, dried (MgSO4) and concentrated in vacuo. To the residue was added 10 ml of DCM, some solid precipitated out. After filtration, some yellow solid was afforded. The filtrate was purified by chromatography on silica gel (0-30% EtOAc in hexane) to isolate 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.375 g, 3.47 mmol, 53% overall) as a yellow solid. MS ESI calc'd. for C25H19ClN3 [M+H]+ 396, found 396.