Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH3:20])=[N:17]2)=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:20][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc(Cl)cc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2ccc(CBr)nc2c1

Procedure:
A stirred suspension of N-bromosuccinimide (9.0 g), 7-chloroquinaldine (9.0 g), dibenzoylperoxide (0.5 g) in CCl4 (200 ml) at 90° was illuminated with a 225 W sunlamp for 6 hours. The suspension was cooled and passed through a plug of silica gel. The plug of silica gel was washed with 30% ether in hexane and the filtrate was evaporated. Flash chromatography of the residue using 30% ether in hexane afforded the title compound.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH3:7].[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CC(C)([O-])C.[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:7][C:3]1[N:4]=[CH:5][S:6][C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]1
Reactant: Cc1ncsc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ncsc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 207.6 %

Procedure:
A solution of 5-bromo-4-methylthiazole (454 mg, 2.55 mmol), N-Boc-piperazine (940 mg, 5.05 mmol), sodium tert-butoxide (492 mg, 5.12 mmol) and dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-thisopropylphenyl)phenyl]phosphane (BrettPhos, 64.9 mg, 0.121 mmol) in anhydrous 1,4-dioxane (9 mL) was flushed with argon for 3 min. Tris(dibenzylideneacetone)dipalladium(0) (106 mg, 0.116 mmol) was added and the mixture was heated in a sealed flask to 70° C. for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through kieselguhr and the filtrate was concentrated under reduced pressure to yield 1.5 g of a brown oil which was purified by flash chromatography (silica, gradient of 0.5 to 3% methanol in dichloromethane). 267 mg of a light-yellow oil were obtained (0.942 mmol), 37%). MS (ESI) m/z=284.2 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[K+].Cl[C:15]([O:17][CH3:18])=[O:16].Cl>>[CH3:18][O:17][C:15]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1)=[O:16]
Reactant: O=C(O)CCC1CCNCC1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COC(=O)N1CCC(CCC(=O)O)CC1

Procedure:
The solution from step b) was brought to pH 12 with aqueous potassium hydroxide. To this solution was added 21 mL methyl chloroformate (0.27 mol). After the reaction was complete, the solution was brought to pH 1 with 6 N HCl and extracted with dichloromethane. The organic layer was dried with sodium sulfate and the dichloromethane displaced with isopropyl ether. The product was isolated as a solid by filtration. Yield 39 gm, 84%. M.p. 89-90° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1(=O)[O:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]1[CH2:10][CH2:11][CH2:12][C:13]1=[O:14]
Reactant: O=C1CCCO1
Reactant: Nc1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C1CCCN1c1ccc(F)cc1F
Temperature: 100 °C

Procedure:
A mixture of 64.6 g of 2,4-difluoroaniline, 51.7 g of butyrolactone, 2 g of p-toluenesulphonic acid and a few drops of water is warmed to reflux (100 ° C.) with stirring. The water which forms is removed by distillation via a vigorous stream of nitrogen. During this operation, the internal temperature increases to 162° over the course of 15 hours. After cooling to room temperature, the mixture is diluted with 100 ml of diethyl ether. The ether solution is washed first with 5% strength HCl and then with 10% strength NaOH, dried and evaporated. The crystalline residue is recrystallized from ethanol. The 1-(2,4-difluorophenyl)pyrrolid-2-one obtained melts at 95°-97°.
Reaction SMILES: [OH-:1].[Na+:2].Cl[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])(=[O:6])=[O:5]>>[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O-:12])=[O:11])([OH:1])(=[O:6])=[O:5].[Na+:2]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: [OH-]
Agent: [Na+]
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 96.5 %

Procedure:
The pH of 345 g of mother liquor from Example 1 is adjusted to 4 with about 60 g of sodium hydroxide. 300 ml of this solution are introduced together with 264.5 g of 3-(chlorosulfonyl)benzoic acid (water content: 25.7%) (corresponding to 196.5 g (0.89 mol) of 100% 3-(chlorosulfonyl)benzoic acid). The reaction mixture is heated to 100° C. and stirred for a further 45 minutes at this temperature. The mixture is then allowed to cool over about 1 hour to 40° C. Subsequently it is cooled with an ice bath to <5° C. and stirred for a further 30 minutes at this temperature. The precipitated product is filtered off with suction and washed with 256 g of 5% strength sodium chloride solution, prepared from 13.8 g of sodium chloride and 243.2 g of water and cooled to 5° C., in two portions. The filter cake is dried at 100° C./100 torr (13.16 kPa). 192.6 g of sodium 3-sulfobenzoate are obtained with a purity of 96% and a sodium chloride content of 3.2% (corresponding to 184.9 g (0.83 mol) of 100% sodium 3-sulfobenzoate). The yield is 92.6% of theoretical.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH2:30][OH:31])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH2:30][OH:31])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(S(=O)(=O)NCCO)cc1
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Product: CN(c1cc(C(=O)Nc2ccc(S(=O)(=O)NCCO)cc2)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 4-amino-N-(2-hydroxyethyl)benzenesulfonamide (prepared according to the method described by R. N. Misra et al. in Bioorg. Med. Chem. Lett. 2004, 14, 2973-2977), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: CO[C:3](=[O:26])[CH2:4][CH:5]([C:16]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[C:18](Br)[N:17]=1)S(C1C=CC(C)=CC=1)(=O)=O.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:18]2[N:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[NH:22][C:3](=[O:26])[CH2:4][CH2:5]3)[CH:28]=1
Reactant: COC(=O)CC(c1nc(Br)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Reactant: OB(O)c1cccnc1
Product: O=C1CCc2nc(-c3cccnc3)ccc2N1

Procedure:
In analogy to the procedures described for the preparation of example 32 (steps [C] to [D]), the title compound was prepared using 3-(6-bromo-3-nitro-pyridin-2-yl)-3-(toluene-4-sulfonyl)-propionic acid methyl ester and 3-pyridine boronic acid as corresponding starting materials. MS: 226.1 (M+H+).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([N:18]2[CH:22]=[C:21]([C:23]([OH:25])=O)[N:20]=[N:19]2)[CH:14]=[C:15]([F:17])[CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:60]=[N:61][CH:62]=[C:63]([Cl:65])[CH:64]=2)[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[Cl:65][C:63]1[CH:64]=[C:59]([O:58][CH:55]2[CH2:54][CH2:53][N:52]([C:50](=[O:51])[CH2:49][NH:48][C:23]([C:21]3[N:20]=[N:19][N:18]([C:13]4[CH:14]=[C:15]([F:17])[CH:16]=[C:11]([F:10])[CH:12]=4)[CH:22]=3)=[O:25])[CH2:57][CH2:56]2)[CH:60]=[N:61][CH:62]=1
Reactant: O=C(O)c1cn(-c2cc(F)cc(F)c2)nn1
Reactant: NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1)c1cn(-c2cc(F)cc(F)c2)nn1
Reaction time: 0.03 h
Yield: 54.4 %

Procedure:
DIPEA (149.2 mg, 1.15 mmol) was added to a stirred solution of 1-(3,5-difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (65 mg, 0.28 mmol) in DMF (2 mL) followed by HOBt (43 mg, 0.31 mmol) and EDCI (110 mg, 0.57 mmol). After 2 minutes of stirring, 2-amino-1-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (88.4 mg, 0.28 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and the precipitate was collected. The crude solid was purified by recrystallisation from a mixture of DCM and hexane to afford 95 mg (54.4% Yield) of 1-(3,5-difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 477.12, 98.45%. 1H NMR (300 MHz, DMSO-d6): δ 9.5 (s, 1H), 8.5 (t, 1H), 8.3 (d, 1H), 8.2 (d, 1H), 7.9 (d, 2H), 7.75 (t, 1H), 7.58-7.5 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 4.0-3.8 (m, 1H), 3.8-3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 2.1-1.9 (m, 2H), 1.9-1.5 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[C:13](=[N:21]O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:24]1([CH2:34][NH2:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:35][C:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)=[N:21][C:13]=2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: NCc1cccc2ccccc12
Reactant: CC(=O)OCc1ccc(C(=O)C(=NO)C(=O)OC(C)(C)C)cc1
Product: CC(=O)OCc1ccc(-c2[nH]c(-c3cccc4ccccc34)nc2C(=O)OC(C)(C)C)cc1
Yield: 39.7 %

Procedure:
tert-Butyl 3-(4-acetoxymethylphenyl)-2-hydroxyimino-3-oxopropionate (19.2 g) and 1-naphthylmethylamine (11.3 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give tert-butyl 5-(4-acetoxymethylphenyl)-2-(1-naphthyl)-imidazole-4-carboxylate (10.5 g), melting point 162-164° C. (2) tert-Butyl 5-(4-acetoxymethylphenyl)-2-(1-naphthyl)imidazole-4-carboxylate (10.5 g) was reacted and treated in the same manner as in Example 31 to give 5-(4-acetoxymethylphenyl)-2-(1-naphthyl)-N-(2-thiazolyl)imidazole-4-carboxamide (6.62 g), melting point 197-199° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C@H:12]([O:40]C(=O)C)[C@H:13]1[O:17][C:16](=[O:18])[N:15]([C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[C:24]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[NH:25][C:26]3=[O:29])=[CH:21][CH:20]=2)[CH2:14]1)(=O)C.Cl>CO>[OH:40][C@H:12]([C@H:13]1[O:17][C:16](=[O:18])[N:15]([C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[C:24]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:37])([F:39])[F:38])[NH:25][C:26]3=[O:29])=[CH:21][CH:20]=2)[CH2:14]1)[CH2:11][OH:10]
Reactant: CC(=O)OC[C@H](OC(C)=O)[C@@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
Potassium carbonate (17 mg, 0.121 mmol) was added to a methanol solution (2 ml) that contained the (S)-2-acetoxy-2-{(S)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-yl}ethyl acetate (25 mg, mmol) obtained in step B. The obtained mixture was stirred at a room temperature for 1.5 hours. Thereafter, the reaction solution was neutralized with 1 N hydrochloric acid, and the resultant was then extracted with methylene chloride. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1) and preparative HPLC, so as to obtain 7-[(S)-5-((S)-1,2-dihydroxyethyl)-2-oxooxazolidin-3-yl]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (6.7 mg, 32%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]O)=O.O.Cl[CH2:14]Cl>>[CH2:3]([C@@H:4]([CH2:9][CH2:10][CH2:11][CH3:14])[CH2:5][OH:7])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCCl
Solvent: O
Product: CCCC[C@H](CC)CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1000 ml of phosphate buffer (0.1 M, HK2PO4/H2KPO4 with 95/5 in mol/mol, pH˜8.0) was added yeast (200 g, Sigma Aldrich) and sucrose (10 g, Thermo FiSEHr Scientific Inc.), and the mixture was stirred for 2 hrs. Then pentane (1500 ml) was added followed by adding 2-ethylidenehexanal (10.0 g, 79.2 mmol, TCI). The mixture was stirred for 2 days. Then the mixture was divided into batches of 300 ml each, and separated by centrifuging, and the yeast and water phase was extracted with pentane. After volatiles were removed, 12.0 g of yellowish oil was collected, with the crude product yield over 100%. GC and GC/MS analysis indicated an impurity of about 40% (˜4.8 g) while starting materials were less than 2%. The impurity was judged to be 2-ethylidenehexan-1-ol based on GC/MS results (with m/z of 128). The crude product was dissolved in dichloromethane and cooled down to 0° C., meta-chloroperoxybenzoic acid (MCPBA) (6.46 g, 37.5 mmol) was added, and the reaction was stirred at 0° C. for 1 hr. Then the reaction was poured into deionized water, the organic phase was extracted with dichlormethane, and then the organic phase was dried over sodium sulfate. The volatiles of the organic phase were removed under reduced pressure, and the resulted dark oil was separated by flash column chromatography with pentane/dichloromethane (1/1 in v/v). The over all yield was 50%. 1H NMR (500 MHz, CDCl3) δ (ppm): 3.58 (d, J=5.05 Hz, 2H), 1.44-1.24 (m, 10H), 0.92 (t, J=7.15 Hz, 6H). GC/MS: calcd for C8H18O (m/z): 130.14. found 130. [α]D=+3.1° (Concentration of 1.2 g/100 ml in acetone, 25° C.). ([Ref]: [α]D=+ 3.1°, e.e. =96%, C. R. G. Grenier, S. J. George, T. J. Joncheray, E. W. Meijer, and J. R. Reynolds, J. Am. Chem. Soc. 2007, 129, 10694-10699.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:37][CH2:38][CH:39]4[CH2:41][CH2:40]4)=[C:17]([NH:20][C:21](=[O:36])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH:26]4[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51].C(Cl)Cl.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:37][CH2:38][CH:39]4[CH2:40][CH2:41]4)=[C:17]([NH:20][C:21](=[O:36])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:27][CH:26]4[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C1CNCCN1CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)C1CN(S(C)(=O)=O)CCN1CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred mixture of 500 mg 4-[(3-chloro-4-fluoro-phenyl)-amino]-6-({4-[2-(ethoxycarbonyl)-piperazin-1-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline and 0.20 ml triethylamine in 5 ml of methylene chloride is cooled in an ice/water bath, and 80 μl of methanesulfonyl chloride are added dropwise. The reaction mixture is stirred for one hour at 0° C. and another two hours at room temperature. Aqueous work-up followed by column chromatography on silica gel with methylene chloride/methanol (97:2) gives the title compound as a slightly yellow solid. Yield: 395 mg (70% of theory), Melting point: 170-173° C. Mass spectrum (ESI+): m/z=661, 663 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([CH3:18])([CH3:17])[C:4]=2[NH:5][N:6]=1.Cl[C:20]1[C:25]([F:26])=[CH:24][N:23]=[C:22]([CH2:27][O:28][CH3:29])[N:21]=1.[K].OP(O)(O)=O>CS(C)=O>[F:26][C:25]1[C:20]([NH:1][C:2]2[C:3]3[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([CH3:18])([CH3:17])[C:4]=3[NH:5][N:6]=2)=[N:21][C:22]([CH2:27][O:28][CH3:29])=[N:23][CH:24]=1
Reactant: COCc1ncc(F)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1Cc2c(N)n[nH]c2C1(C)C
Agent: O=P(O)(O)O
Agent: [K]
Solvent: CS(C)=O
Product: COCc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)OC(C)(C)C)C3(C)C)n1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (3.00 g, 11.6 mmol) and 4-chloro-5-fluoro-2-(methoxymethyl)pyrimidine (2.06 g, 11.6 mmol) in DMSO (8 mL) was added potassium dihygrogenphosphate (1.58 g, 2.3 mmol) followed by H3PO4 (0.29 g, 2.3 mmol). The reaction was place in a 90° C. oil bath and heated for 20 h. The crude reaction was cooled to room temperature then poured into ice cold NaHCO3 (60 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine then dried (MgSO4), filtered and concentrated. The crude solid was triturated with EtOAc to provide the title compound N1(i) as a white solid (3.2 g, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 1.59 (s, 3H), 1.61 (s, 3H), 3.34 (s, 3H), 4.29-4.44 (m, 2H), 4.45-4.64 (m, 2H), 8.32 (d, J=3.20 Hz, 1H), 10.25 (br. s., 1H), 12.24 (br. s., 1H). Mass Spectrum: Calcd for C18H25FN6O3(M+H): 393. Found: 393.
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([CH:39]([OH:48])[C:40]2[N:41]=[CH:42][N:43]3[CH:47]=[CH:46][S:45][C:44]=23)[CH2:37][C@H:36]([S:49][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:62]([C@H:63]([O:65][Si](C(C)(C)C)(C)C)[CH3:64])[C:61](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]>C1COCC1.C(OCC)(=O)C>[CH2:28]([O:31][C:32]([N:34]1[C@H:38]([CH:39]([OH:48])[C:40]2[N:41]=[CH:42][N:43]3[CH:47]=[CH:46][S:45][C:44]=23)[CH2:37][C@H:36]([S:49][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[CH2:35]1)=[O:33])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncn4ccsc34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncn4ccsc34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
Acetic acid (0.60 ml) and 3.5 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of 491 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-7-yl)methyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate (a diastereomer mixture) in 10.5 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 16 hr. The reaction solution is diluted with 100 ml of ethyl acetate, and the diluted solution is successively washed with a 5% aqueous sodium hydrogencarbonate solution and saturated saline and dried over anhydrous magnesium sulfate, followed by filtration and the removal of the solvent by evaporation to give a dark yellow oil. This oil is purified by column chromatography on silica gel (ethyl acetate:methanol=95:5) to give 353 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-7-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (a diastereomer mixture) as a light yellow amorphous material.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH2:10].[O:11]1CCOC[CH2:12]1>>[N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[C:12]=[O:11]
Reactant: NC1Cc2ccccc2C1
Reactant: C1COCCO1
Product: O=C=NC1Cc2ccccc2C1

Procedure:
A solution of 1.53 g (11.5 mmol) indan-2-ylamine and 1.39 mL (11.5 mmol) in 40 mL dry dioxane is stirred for 2 hours at 70° C. under argon atmosphere and then concentrated under vacuum.
Reaction SMILES: [C:1]1([CH3:50])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH2:14][CH2:15][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:53][N:54]([CH2:58][CH2:59]Cl)[CH2:55][CH2:56]Cl>CN(C=O)C>[CH3:53][N:54]1[CH2:58][CH2:59][N:19]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:18][CH2:17][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:31])=[O:32])[CH2:15][CH2:14][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:41])=[O:42])[CH2:12][CH2:11][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:50])=[CH:2][CH:3]=2)(=[O:8])=[O:9])[CH2:56][CH2:55]1
Reactant: Cc1ccc(S(=O)(=O)NCCN(CCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CN(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN(C)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a stirred solution of 1,4,7,10-tetra(p-toluenesulfonyl)-1,4,7,10-tetraazadecane prepared as in Example 15B (66.5 g, 0.0872 mole) in anhydrous DMF (1 l) was added sodium hydride (5.22 g-80% in mineral oil, 0.174 mole) in portions under a dry nitrogen blanket. The resulting mixture was stirred for 30 minutes under a dry argon atmosphere. The solution was then heated to 100° C. and a solution of N-methylbis(2-chloroethyl)amine freshly prepared as in Example 15A (13.6 g, 0.0872 mole) in anhydrous DMF (200 ml) was added dropwise over a 1.5 h period, maintaining the temperature at 100° C. After stirring an additional 45 minutes at 100° C., the solution was concentrated in vacuo to a volume of 750 ml. H2O was slowly added at room temperature to crystallize the product. The resulting brown solid was filtered, washed thoroughly with H2O and dried in vacuo over P2O5 to give 62.9 g (85% yield) of the crude product as a brown solid. The product was purified by crystallization from DMF-H2O to give a yellow solid: mp 170°-1° C.; 1H NMR (CDCl3) δ 2.15 (s, 3 H), 2.43 (s, 6 H), 2.44 (s, 6 H), 2.51 (t, J=5.5 Hz, 4 H), 3.15 (t, J=5.5 Hz, 4 H), 3.29 (m, 8 H), 3.36 (s, 4 H), 7.32 (m, 8 H), 7.69 (m, 8 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1)=[O:8].[N:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[C:19]=[O:20]>C1C=CC=CC=1>[CH3:17][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([NH:18][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:20])=[CH:16][C:6]=1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[N:14][CH:13]=[N:12][CH:11]=1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cncnc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cncnc1
Temperature: 75 °C

Procedure:
To a suspension of 5-amino-2-methyl-N-(pyrimidin-5-yl)benzamide 26 (0.068 g, 0.30 mmol) in benzene (5 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (0.046 mL, 0.33 mmol). The reaction was heated at 75° C. for 2 hours, producing a solid precipitate. The mixture was concentrated and chromatographed on silica gel with 94/6 CH2Cl2/MeOH to afford 1-(4-methyl-3-(pyrimidin-5-ylcarbamoyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea 27 as a white solid. MS m/z: found 416 [MH+], calc. for C20H16F3N5O2=415.13.