Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:17]1([C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>CO>[C:17]1([C:23]2([C:29]([O:31][CH3:6])=[O:30])[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCNCC1
Temperature: 0 °C

Procedure:
270 ml of methanol are taken. 10.6 ml sulphuric acid and 25 g 4-phenyl-4-piperidine-carboxylic acid p-toluenesulphonic acid are added with stirring. The reaction mixture is refluxed for 9 h, cooled and carefully poured onto a mixture of ice water and 10 M NaOH. The precipitated solid is suction filtered, washed with water and dried. 11.2 g (V-15) are obtained as a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[C:25]([O:29][C:30](=[O:38])[N:31]([CH3:37])[CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>CN1C(=O)CCC1.CC(OC)(C)C>[C:25]([O:29][C:30](=[O:38])[N:31]([CH:32]1[CH2:36][CH2:35][N:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][C:21]=4[F:22])[N:18]=[CH:17][CH:16]=[CH:15]5)=[CH:9][N:10]=3)[N:7]=2)[CH2:33]1)[CH3:37])([CH3:28])([CH3:26])[CH3:27]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN1CCCC1=O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)C1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 150 mg, 0.474 mmol), KF (139 mg, 2.372 mmol) and (rac)-methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester (285 mg, 1.423 mmol) were suspended in NMP (1.5 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with TBME and washed with water (3×). The aqueous phases were further extracted with TBME (1×). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized in Et2O to afford the title compound as a beige solid (tR 3.91 min (conditions 13), MH+=477).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][C:12]#[N:13])[CH:6]=[CH:7][CH:8]=1.N.[H][H]>[Ni].CO>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: N#CCCNc1cccc(C(F)(F)F)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCNc1cccc(C(F)(F)F)c1
Yield: 100 %

Procedure:
A mixture of 13.6 parts of 3-[[3-(trifloromethyl)phenyl]amino]propanenitrile and 400 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at a temperature below 20° C. with 3 parts of Raney Nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 13 parts (100%) of N1 -[3-(trifluoromethyl)phenyl]-1,3-propanediamine as a residue (int. 106).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl.[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][C:35](O)=[O:36]>>[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][C:35]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]=2[CH2:22]1)=[O:36]
Reactant: CN(C)CCC(=O)O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)CCN(C)C)CC3)cc1

Procedure:
Method as described for example 17 using (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea (example 12) and 3-dimethylamino propionic acid hydrochloride as starting materials. Purified by prep HPLC (low pH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1oc(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c1OCc1ccccc1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: Cn1c(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Yield: 78.57 %

Procedure:
3-Benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-05) (1.62 g, 78.57%) was synthesized as a yellow solid from 3-benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-05) (2.0 g, 4.45 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([OH:16])([CH3:17])[CH3:14])=[N:3][CH:4]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 2,5-dibromopyridine in toluene (12 ml/mmol) cooled to −78° C. was added n-butyllithium 2.5M in hexanes (1.05 eq) and the resulting mixture was stirred in the cold for 2.5 hours. Acetone (2 eq) was added and stirring was continued for 1.5 h. After quenching with saturated aqueous ammonium chloride solution, the mixture was warmed to room temperature and partitioned between ethyl acetate and water. The product from the organic phase was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford the 5-Bromo-2-(1-hydroxy-1-methylethyl) pyridine compound as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+].[CH3:49][S:50]([CH3:52])=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:49][S:50][CH3:52])[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OCSC)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (25 mg, 0.054 mmol) in DMSO (0.2 mL) was added a mixture of acetic acid and acetic anhydride (1:5.6) (0.17 mL). After stirring for 1.5 h at room temperature it was held at 40° C. for 5 h. It was cooled to room temperature and stirred for 16 h. The mixture was cooled in ice-bath and NaHCO3 solution was added carefully. It was extracted with ether. The extract was washed with water and brine, dried over MgSO4 and evaporated. Pure 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(trans-4-methylsulfanylmethoxy-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester was obtained by chromatography over silica gel (hexane:EtOAc=−4:1) (22 mg, 77%).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])#[N:2].Br[CH2:13][CH2:14]Br.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>ClCCl>[C:4]([C:3]1([C:1]#[N:2])[CH2:14][CH2:13]1)(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: BrCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: N#CC1(C(=O)c2ccccc2)CC1
Yield: 20.9 %

Procedure:
1 g (7 mmol) of α-cyanoacetophenone, 8 g (43 mmol) of 1,2-dibromoethane, 0.1 g (0.4 mmol) of 18-crown-6 and 4 g (69 mmol) of potassium fluoride are heated under reflux for 18 h as a heterogeneous system in 10 ml of dichloromethane. After cooling, the mixture is filtered, the organic phase is washed with H2O and the solvent is evaporated in vacuo after drying over Na2SO4. The residue is chromatographed on a silica gel using CH2Cl2. 0.25 g (20% of theory) of 1-benzoyl-1-cyanocyclopropane are obtained in this manner as a colorless oil,
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]1([CH:21]=[CH:20][C:18]([OH:19])=[CH:17][CH:16]=1)[OH:15]>>[OH:15][C:14]1[CH:21]=[CH:20][C:18]([O:19][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(O)cc1
Product: O=C(O)c1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid was reacted with hydroquinone to produce 4-(4-Hydroxy-phenoxy)-3-nitro-benzoic acid according to the procedure of Example 37A, which was treated sequentially with 3-Bromo-phenylamine using the procedure from Example 37B and reduced using the procedure from Example 37C to provide the title product.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=1[F:40])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:27]([F:30])([F:29])[F:28])=[N:19][C:20]([C:21](=[O:26])[NH:22][CH:23]3[CH2:25][CH2:24]3)=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:42]>C(OCC)(=O)C>[ClH:42].[CH:23]1([NH:22][C:21]([C:20]2[N:19]=[C:18]([C:27]([F:28])([F:30])[F:29])[N:15]3[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:31][C:32]4[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=4[F:40])[CH2:13][C:14]=23)=[O:26])[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NC3CC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NC3CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 95 %

Procedure:
(R)-[3-(1-Cyclopropylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 15a (0.1 g, 0.16 mmol) was added to a solution of 2.2 N hydrochloric acid in 5 mL of ethyl acetate. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid cyclopropylamide hydrochloride 15 (82 mg, yield 95%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([N:26]=[C:27]=[S:28])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Na+].[NH2:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([OH:55])=[CH:36][C:37]([S:41]([NH:44][C:45]3[CH:46]=[C:47]([S:51]([O-:54])(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=3)(=[O:43])=[O:42])=[CH:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:17]=[C:18]3[C:23]([CH:22]=[CH:21][C:20]([NH:26][C:27]([NH:30][C:31]4[CH:40]=[C:39]5[C:34]([C:35]([OH:55])=[CH:36][C:37]([S:41]([NH:44][C:45]6[CH:46]=[C:47]([S:51]([OH:54])(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=6)(=[O:42])=[O:43])=[CH:38]5)=[CH:33][CH:32]=4)=[S:28])=[CH:19]3)=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N=C=S)cc3c2)ccc1Cl
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)Nc3cccc(S(=O)(=O)[O-])c3)cc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(NC(=S)Nc4ccc5c(O)cc(S(=O)(=O)Nc6cccc(S(=O)(=O)O)c6)cc5c4)cc3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 170 mg (0.39 mmol) of compound 135 dissolved in 5 mL of DMF was added a solution of 100 mg (0.25 mmol) of compound 18 in 5 mL of DMF. The reaction was allowed to stir at ambient temperature. After 4 days, the DMF was removed by rotary evaporation and kept under high vacuum to remove traces of DMF. Then, the resulting residue was treated with dichloromethane (50 mL) and sonicated to form a suspension. The solid, insoluble product was collected by vacuum filtration. This solid was dissolved in methanol and then the methanol was removed by rotary evaporation. The resulting solid was again treated with dichloromethane, sonicated, and collected by vacuum filtration. This provided 172 mg of an orange solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].CO.[CH3:11][Si](C=[N+]=[N-])(C)C>C(OCC)C>[CH3:11][O:7][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: C=CCCCC(=O)OC

Procedure:
Hex-5-enoic acid methyl ester was prepared as follows. Hex-5-enoic acid (2.00 g, 17.5 mmol) was dissolved in diethyl ether (8 mL) and methanol (4 mL) and cooled to 0° C. To this solution was added 2.0 M Trimethylsilyl diazomethane (9 mL) dropwise. It was noted that a yellow TMS-diazomethane solution dissipates upon stirring with the reaction mixture, and the reaction is deemed complete when the yellow color persists. Caution should be observed, as the reaction is associated with vigorous gas evolution. When the yellow color persists in the reaction mixture, TLC analysis was conducted and confirmed consumption of the acid. The solvent was evaporated under reduced pressure carefully (product is somewhat volatile) and replaced with ethyl acetate. The solution was washed with saturated NaHCO3, dried, and the filtrate was used directly in the next step. 1H NMR (400 MHz) CDCl3 δ 5.45 (m, 1H), δ 4.9 (m, 2H), δ 3.65 (s, 3H), δ 2.20 (t, 2H), δ 2.05 (m, 2H), δ 1.70 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:7]=1[CH2:8][N:9]1[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:17])[CH2:12][CH2:11][C@H:10]1[C:34](O)=[O:35].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:3][CH2:2][CH2:1][NH:4][C:34]([C@H:10]1[N:9]([CH2:8][C:7]2[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:6]=2[F:5])[CH2:14][C@H:13]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:17])[CH2:12][CH2:11]1)=[O:35]
Reactant: COc1cccc(F)c1CN1C[C@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CC[C@H]1C(=O)O
Reactant: NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(F)c1CN1C[C@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CC[C@H]1C(=O)NCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
ethane-1,2-diamine (18 mg, 0.290 mmol) was added to a stirred mixture of (2S,5R)-1-(2-fluoro-6-methoxybenzyl)-5-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)-piperidine-2-carboxylic acid (50 mg, 0.097 mmol), N,N-DIISOPROPYLETHYL-AMINE (0.084 ml, 0.483 mmol), HATU (73.5 mg, 0.193 mmol) in dimethylformamide and the mixture was stirred at room temperature for Overnight. The reaction was rotovap to dryness and the residue was purified by column chromatography on silica gel Isolute Flash Si; 50 g prepacked, eluting with 5% MeOH/NH3(2M)CH2Cl2 to give the desired (48.1 mg, 0.085 mmol, 88% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12.[Li]CCCC.C1(S(N([F:52])S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1>C1COCC1>[F:52][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CN1CCn2c(C(F)(F)F)cc(Br)c2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCn2c(C(F)(F)F)cc(F)c2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A solution of tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (15.0 g, 33.2 mmol) in THF (200 mL) was purged with Argon for 5 min. The mixture was cooled to −78° C. before nBuLi (42.5 mL of 1.6 M, 68 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min before a solution of N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (20.9 g, 66.3 mmol) in THF (100 mL) was added dropwise. The mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with sat. aq. NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated to dryness. CH2Cl2 was added and the solid was removed via filtration. The filtrate was concentrated to dryness and the residue was purified by column chromatography (10-20% EtOAc-Hex) to provide tert-butyl 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5.52 g, 43%) as a light brown oil that solidified upon standing. ESI-MS m/z calc. 391.4, found 392.5 (M+1)+; Retention time: 1.35 minutes (3 minute run).
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[O:17])[N:9]([CH3:18])[C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28]Br>CN(C=O)C>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][N:14]1[C:13]2[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[O:17])[N:9]([CH3:18])[C:8]=2[N:7]=[C:6]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1c(=O)c2[nH]c(C3CCCC3)nc2n(C)c1=O
Reactant: Fc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(C3CCCC3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 60 °C
Yield: 14.7 %

Procedure:
A solution of 8-cyclopentyl-1,3-dimethylxanthine (100 mg, 0.40 mmol) and K2CO3 (80 mg, 0.58 mmol) was treated with 2-chloro-6-fluorobenzyl bromide (142 mg, 0.64 mmol) dissolved in 400 μL DMF. The reaction mixture was sealed and heated to 60° C. for 24 hrs. The reaction mixture was cooled and purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with EtOAc:hexane (1:1) to give 23 mg (14% yield) of the title compound as a white solid: 1H NMR (CDCl3, 400 MHz) 7.29-7.11 (m, 2H), 7.01-6.85 (m, 1H), 5.86 (s, 2H), 3.54 (s, 3H), 3.38 (s, 3H); 3.02-2.81 (m, 1H), 1.83-1.43 (m, 8H); MS (ESP+) m/e 391 (MH+); TLC(EtOAc:hexanes/1:1) Rf=0.58.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:9]([O:12][CH2:13][CH:14]([O:20][CH2:21]OC(=O)C)[CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:9]([O:12][CH2:13][CH:14]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:20][CH2:21][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2])(=[O:11])[CH3:10]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(=O)OCOC(COC(C)=O)COC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(=O)OCC(COC(C)=O)OCn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.1 %

Procedure:
5.6 g of 2-nitroimidazol, 12.4 g of 1,3-diacetoxy-2-acetoxymethoxypropane and 0.5 g of p-toluenesulfonic acid monohydrate were placed in a flask connected with a trap for reducing pressure by an aspirator. The flask was heated by oil bath of 130°-140° C. under reduced pressure while stirred. Acetic acid was distilled out as the reaction proceeded. In about 15 minutes, the reaction was completed. After cooling down to room temperature, the content was added with about 300 ml ethyl acetate and subjected to extraction. The extract was washed with saturated aqueous sodium hydrogen carbonate, and with water in this order. Then it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by separable high performance liquid chromatography through silica gel columns using a mixture solvent (ethyl acetate - benzene) as an eluate to obtain 13.3 g of the title compound as a viscous oil material (yield: 88.6%).
Reaction SMILES: C(OC(C)C)(C)C.[F:8][C:9]([F:25])([F:24])[C:10]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:23])([OH:15])[C:11]([F:14])([F:13])[F:12].[H][H]>[Ru].O>[F:8][C:9]([F:24])([F:25])[C:10]([CH:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH:17]1[OH:23])([OH:15])[C:11]([F:12])([F:14])[F:13]
Reactant: [H][H]
Reactant: Oc1ccc(C(O)(C(F)(F)F)C(F)(F)F)c(O)c1
Agent: [Ru]
Solvent: O
Solvent: CC(C)OC(C)C
Product: OC1CCC(C(O)(C(F)(F)F)C(F)(F)F)C(O)C1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
A 2,000 ml inner capacity of pressure-resistant reactor having a stirrer and a thermometer and formed of SUS316 was charged with 800 ml of diisopropyl ether, 350 g (1.27 mol) of Compound 6 and 17.5 g of 5% Ru/C (a substance containing 50% of water, produced by N.E. CHEMCAT), and then closed. Thereafter, stirring was started and then the interior of the reactor was substituted with hydrogen, followed by setting hydrogen pressure at 3.0 MPa. The temperature of the reactor was increased up to 130° C., upon which stirring was continued for 20 hours.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([CH:12]2[N:17](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:16][CH2:15][N:14]([C:31]([C@@H:33]3[CH2:37][C@H:36]([S:38][C:39]4[C@H:40]([CH3:63])[C@@H:41]5[C@@H:58]([C@H:59]([OH:61])[CH3:60])[C:57](=[O:62])[N:42]5[C:43]=4[C:44]([O:46]CC4C=CC([N+]([O-])=O)=CC=4)=[O:45])[CH2:35][N:34]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:32])[CH2:13]2)=[O:11])=CC=1)([O-])=O>O1CCCC1.O>[C:10]([CH:12]1[NH:17][CH2:16][CH2:15][N:14]([C:31]([C@@H:33]2[CH2:37][C@H:36]([S:38][C:39]3[C@H:40]([CH3:63])[C@@H:41]4[C@@H:58]([C@H:59]([OH:61])[CH3:60])[C:57](=[O:62])[N:42]4[C:43]=3[C:44]([OH:46])=[O:45])[CH2:35][NH:34]2)=[O:32])[CH2:13]1)([OH:11])=[O:9]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC(C(=O)O)C4)C3)[C@H](C)[C@H]12
Yield: 51.2 %

Procedure:
160 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[3-(4-nitrobenzyloxycarbonyl)-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 3 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 160 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 35 mg of the title compound, as a powder.