Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:11](Cl)=[O:12].[CH2:18]([O:20][C:21]([C@:23]1([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:28]([NH2:29])[CH2:27][C@@H:26]2[C@H:24]1[C@@:25]2([F:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22])[CH3:19]>C(Cl)(Cl)Cl>[CH2:18]([O:20][C:21]([C@:23]1([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@H:28]([NH:29][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:8]([Cl:7])[CH:9]=2)[CH2:27][C@@H:26]2[C@H:24]1[C@@:25]2([F:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22])[CH3:19]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](NC(=O)c3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
7.3 μL of pyridine and 14 mg of 3,4-dichlorobenzoyl chloride were added to 17 mg of (1R,2R,3R,5R,6R)-3-amino-2-t-butoxycarbonylamino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 0.17 mL of chloroform, and the mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent:chloroform-ethanol=100:1), thereby yielding 21 mg of (1R,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzoylamino)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester
Reaction SMILES: [C:1]([N:8]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:18](Br)[CH:19]=[CH2:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:32]1[CH2:36]OC[CH2:33]1>CN1C(=O)N(C)CCC1>[C:1]([N:8]1[CH2:16][C:15](=[O:17])[C:14]([CH2:36][CH:32]=[CH2:33])([CH2:18][CH:19]=[CH2:20])[C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: C=CCBr
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Product: C=CCC1(CC=C)C(=O)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of N-(BOC)-4-oxo-(L)-proline, methyl ester (0.197 g) in 3 mL of THF and 1 mL of DMPU was added 0.28 mL of allyl bromide. The reaction mixture was cooled to −78° C. and 2.0 mL of LiHMDS was dropwise introduced into the reaction. The mixture was stirred at −78° C. for 2 h and then was allowed to warm to rt and stirred under nitrogen overnight. The reaction was quenched with saturated NH4Cl and diluted with water. The mixture was extracted with Et2O (3×). The combined Et2O layers were washed with water, brine and dried over anhydrous Na2SO4. After concentration in vacuo, the crude product was purified by flash column chomatography on silica gel eluted with 5%-10% EtOAc/Hexane to isolate 0.099 g of N-(BOC)-3,3-diallyl-4-oxoproline, methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-])=O>C1COCC1.[Pd]>[NH2:13][C:3]1[CH:4]=[C:5]([S:8]([NH:11][CH3:12])(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CNS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(F)c(N)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a mixture of 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (1.6 g, 6.83 mmol) in THF (50 mL) under nitrogen, Pd/C (0.600 g) was added. The flask was then evacuated and recharged with hydrogen. The resulting mixture was allowed to stir under a hydrogen atmosphere overnight at 50° C. The mixture was then filtered and concentrated to afford 3-amino-4-fluoro-N-methylbenzenesulfonamide (1.25 g, 89%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.26 (q, J=4.85 Hz, 1H), 7.13-7.22 (m, 2H), 6.90 (ddd, J=2.38, 4.27, 8.41 Hz, 1H), 5.63 (s, 2H), 2.40 (d, J=5.02 Hz, 3H); MS (m/z) 205.1 (M+H+)
Reaction SMILES: [H][H].[CH3:3][C:4]1[NH:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=2)[C:6](=[O:19])[CH:5]=1>[Pd].O1CCCC1>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([N:7]2[C:6](=[O:19])[CH:5]=[C:4]([CH3:3])[NH:8]2)=[CH:10][C:11]=1[CH3:18]
Reactant: [H][H]
Reactant: Cc1cc(=O)n(-c2ccc([N+](=O)[O-])c(C)c2)[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(=O)n(-c2ccc(N)c(C)c2)[nH]1

Procedure:
Hydrogen was introduced under atmospheric pressure into the mixture of 350 mg of 5-methyl-2-(3-methyl-4-nitrophenyl)-1,2-dihydropyrazol-3-one, 70 mg of Pd/C and 50 ml of tetrahydrofuran until the theoretical uptake. Afterwards, the catalyst was filtered off with suction and the mixture was concentrated to dryness under reduced pressure and the residue was stirred in t-butyl methyl ether. The solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:12]1([NH:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:18]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[O-:19])[CH3:2]
Reactant: CCOc1ccccc1C=O
Reactant: ONC1CCCCC1
Product: CCOc1ccccc1C=[N+]([O-])C1CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 2-ethoxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 89% yield as a solid, m.p. 54.8° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC)=[N+:2]=[N-:3].[CH2:22](C1C=CC(C(Cl)=O)=CC=1)[CH2:23]CCC.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:23][CH:22]=1)=[N+:2]=[N-:3]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 76 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 4-pentylbenzoyl chloride (0.283 g, 1.35 mmol) was reacted with 2-azidoethanamine (0.116 g, 1.35 mmol) and triethylamine (0.273 g, 2.69 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-pentylbenzamide (0.267 g, 76% yield). 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J=8.1 Hz, 2H), δ 7.61 (t, J=5.1 Hz, 1H), δ 7.15 (d, J=8.4 Hz, 2H), δ 3.54 (q, J=5.7, 5.1 Hz, 2H), δ 3.44 (t, J=5.7 Hz, 2H), δ 2.58 (t, J=7.5 Hz, 2H), δ 1.57 (m, 2H), δ 1.26 (m, 4H), δ 0.86 (t, J=6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.6, 147.2, 131.7, 128.7, 127.5, 50.8, 39.7, 35.9, 31.6, 31.1, 22.7, 14.2 ppm; HRMS (ESI) calcd for C14H20N4O (M+) 260.1637. found 260.1632.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH2:29][CH:30]=[CH2:31])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH2:29][CH:30]=[CH2:31])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.6 g) and conc. hydrochloric acid (1.5 ml) in methanol (30 ml) was stirred at ambient temperature for 2 hours. After evaporation of the reaction mixture, thereto was added a saturated aqueous solution of sodium bicarbonate, followed by removing the insoluble substance by filtration. The filtrate was adjusted to pH 3 with 10% hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.25 g).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C>[CH2:17]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(O)cc1
Reaction time: 8 h

Procedure:
A solution of hydroquinone (33.00 g, 0.30 mol) and potassium carbonate (45.6 g, 0.33 mol) in dry DMF (250 mL) was stirred at 40° C. for minutes. Allyl bromide (5.20 mL, 0.06 mol) was added and the reaction was stirred overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with hexane/ethyl acetate (4:1) to afford 4-allyloxyphenol.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[N:8]=[C:9](Cl)[C:10]2[S:15][CH:14]=[CH:13][C:11]=2[N:12]=1.Cl.[CH3:18][O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]>O1CCCC1>[CH3:18][O:19][C:20]([C:22]1[C:23]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][NH:35][C:9]3[C:10]4[S:15][CH:14]=[CH:13][C:11]=4[N:12]=[C:7]([Cl:6])[N:8]=3)=[CH:32][CH:33]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(CNc2nc(Cl)nc3ccsc23)cc1
Yield: 54 %

Procedure:
Sodium acetate (1.2 g), 2,4-dichlorothieno[3,2-d]pyrimidine(0.75 g) and 4'-aminomethyl(1,1'-biphenyl)-2-carboxylic acid methylester hydrochloride (1.02 g) were suspended in 40 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 days at which time all the THF was removed by evaporation. The residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel chromatography (ETOAc/Hexane) to yield the product as a buff powder (0.81 g, 54%) (m.p.=177°-182° C.): 1H NMR (DMSO-d6, 400 MHz) δ8.98 (t, J=6.0 Hz, 1H), 8.19 (d, J=5.4 Hz, 1H), 7.71 (dd, J=1.1; 7.7 Hz, 1H), 7.60 (m, 1H), 7.46 (m, 1H), 7.38 (m, 4H), 7.25 (m, 2H), 4.73 (d, J=5.9 Hz, 2H), 3.58 (s, 3H); positive FAB MS m/e 410 (MH); 376 (M--Cl+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[C:25]([CH:29]=1)[C:26](O)=[O:27])(=[O:20])=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:26](=[O:27])[C:25]2[CH:29]=[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:22]=[CH:23][C:24]=2[C:30]2[S:31][CH:32]=[CH:33][N:34]=2)[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3nccs3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone [189763-57-3] and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 488.5 MH+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:15])([CH3:14])[CH2:9][C:10]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:17]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])N>C(O)=O>[CH3:14][C:8]1([CH3:15])[C:9]2[C:27]3[C:19](=[C:20]([C:21]([OH:23])=[O:22])[CH:24]=[CH:25][CH:26]=3)[NH:17][C:10]=2[C:11]2[C:7]1=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2
Reactant: NNc1ccccc1C(=O)O
Reactant: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: O=CO
Product: CC1(C)c2ccc([N+](=O)[O-])cc2-c2[nH]c3c(C(=O)O)cccc3c21
Yield: 18.5 %

Procedure:
6-Nitro-3,3-dimethyl-1-indanone (0.612 g, 2.98 mmol) [Smith, J. G. et al. Org. Prep. and Proc. Int. 1978, 10(3), 123-131] and 2-hydrazinobenzoic acid hydrochloride (0.562 g, 2.98 mmol) in formic acid (2 mL, 96%) were irradiated for two minutes in a closed cap Teflon vessel of a microwave oven (700 W). The mixture was vacuum filtered, and the crude product was chromatographed (hexane/ethyl acetate 1:1) and triturated with petroleum ether/diethyl ether. Drying in vacuo afforded 0.178 g (19%) of the title compound as a yellow solid: mp 310° C. (dec); 1H NMR (DMSO-d6): δ 13.43 (s, 1H), 11.85 (s, 1H), 8.95 (s, 1H), 8.12 (d, 1H), 7.98 (d, 1H), 7.81 (m, 2H), 7.19 (t, 1H), 1.59 (s, 6H); IR (KBr): 3460, 1670 cm−1; MS (m/z) 322 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:16][CH2:17][CH2:18][O:19]C2CCCCO2)[C:10]2[NH:14][C:13]([NH2:15])=[N:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>CO>[NH2:15][C:13]1[NH:14][C:10]([N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH2:16][CH2:17][CH2:18][OH:19])=[N:11][N:12]=1
Reactant: Nc1nnc(N(CCCOC2CCCCO2)c2ccc(F)c(F)c2)[nH]1
Agent: Cl
Solvent: CO
Product: Nc1nnc(N(CCCO)c2ccc(F)c(F)c2)[nH]1
Temperature: 25 °C
Yield: 103.5 %

Procedure:
To a solution of N3-(3,4-difluorophenyl)-N3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-4H-1,2,4-triazole-3,5-diamine (43 mg, 122 μmol) in methanol (1 mL) was added 2 N aqueous hydrogen chloride solution. The solution was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue was taken up in saturated aqueous sodium hydrogen carbonate solution. It was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield the title compound as a white solid (34 mg, quant) without further purification. MS ISP (m/e): 270.3 (100) [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([Zn]CC)[CH3:10]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:9][CH3:10])=[N:3][CH:4]=1
Reactant: CC[Zn]CC
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 2,5-dibromopyridine (20 g, 84.43 mmol, 1.00 equiv), Pd(PPh3)4 (9.7 g, 8.39 mmol, 0.10 equiv) and tetrahydrofuran (500 mL). To the resulting mixture was then added diethylzinc (46.2 mL) dropwise with stirring at −78° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (10 mL). The resulting mixture was then concentrated under vacuum. The resulting solution was diluted with ethyl acetate (200 mL). The resulting solution was extracted with 4N HCl (2×200 mL) and the aqueous layers combined. The pH value of the solution was adjusted to pH 14 with aqueous LiOH. The resulting solution was extracted with ethyl acetate (2×200 mL) and the organic layers combined. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (4.6/95.4) to yield 5-bromo-2-ethylpyridine as colorless oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C1N2CCN(CC2)C1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([Br:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>C1(C)C=CC=CC=1>[Br:33][C:32]1[CH:34]=[CH:35][C:29]([S:26]([O:1][C@@H:2]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a solution of 1-t-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.15 g, 8.76 mmol) and DABCO (1.57 g, 14.0 mmol) in PhMe (10 mL) at RT was added a solution of brosyl chloride (3.14 g, 12.3 mmol) in PhMe (5 mL). A white precipitate formed, the reaction mixture was stirred for 20 minutes and filtered. The filtrate was partitioned between EtOAc and saturated aqueous NaHCO3; the layers separated; and the organic phase washed with 1 M HCl, water and brine, dried over Na2SO4, filtered and concentrated to afford the title compound as an oil (4.0 g), which was used without further purification. LRMS (M+Na)+ Calcd.: 488; found 488.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:21]=[O:22]>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]2[S:8][C:9]([CH:21]=[O:22])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2cccs2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Oc2ccc(F)cc2)s1
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
To a solution of 2-(4-fluorophenoxy)thiophene (3.66 g, 18.9 mmol) in THF (90 mL) at -78° C., was added butyllithium (7.5 ml of a 2.5M solution in hexanes, 18.9 mmol) dropwise. Upon completion of addition, the mixture was stirred for 20 min. N,N-Dimethylformamide (1.52 g, 20.8 mmol) was then added and the reaction was stirred for 40 min at -78° C. It was then quenched with saturated aqueous NH4Cl (100 mL) and extracted with ethyl acetate (3×100 mL). The organics were combined, dried over MgSO4 and concentrated. The resulting residue was chromatographed (silica gel; 3:1 hexanes, ether) to afford 3.59 g (86%) of 5-(4-fluorophenoxy)-2-thiophenecarboxaldehyde as a slightly orange solid.
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:29][N:30]([CH3:35])[C:31](=[O:34])[CH2:32][Cl:33]>>[ClH:33].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:32][C:31]([N:30]([CH3:35])[CH3:29])=[O:34])[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)C(=O)CCl
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: CN(C)C(=O)CN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m. p. 145° C. and MS: m/e=455.6 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and N,N-dimethyl-2-chioroacetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.OC[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=O)=[CH:26][CH:25]=1.CN([C:37]([O:41]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1>[OH:41][CH2:37][C:29]1[CH:28]=[C:27]([CH2:30][C:31]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:18]4[CH:17]=[N:16][CH:15]=[N:14][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=3)=[O:9])[CH:3]=2)=[O:33])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)Cc1ccc(CO)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(CO)c3)c2)c2cncnc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95, 250 mg, 0.89 mmol), [4-(hydroxymethyl)phenyl]acetic acid (177 mg, 1.06 mmol) and HATU (505 mg, 1.33 mmol) in pyridine (7 mL) was stirred at 50° C. for 3 hours, then at room temperature for 18 hours. The mixture was concentrated in vacuo and azeotroped with toluene. The residue was purified by column chromatography using silica gel (gradient of dichloromethane to dichloromethane/methanol (10:1 to 9:1) to afford the title compound as a gum. This material was dissolved in a 9:1 mixture of dichloromethane/methanol (1.5 mL) and added dropwise to diethyl ether (100 mL), the resulting precipitate was filtered off and dried in vacuo to afford the title compound as a white solid, 412 mg, which was used crude in subsequent reactions.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[C:29](Cl)[N:28]=[CH:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:32][NH2:33]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[C:29]([NH:33][CH3:32])[N:28]=[CH:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(N1CCN(c2cc(Cl)ncn2)CC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: CN
Solvent: CCO
Product: CNc1cc(N2CCN(C(=O)N3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)ncn1

Procedure:
A solution of 1-(4-bromophenylsulphonyl)-4-[1-(6-chloropyrimidin-4-yl)-piperazin-4-ylcarbonyl]piperazine (1.20 g) in 33% methylamine in ethanol (35 ml) was heated at 110° C. in a Carius tube for 16 hours. The mixture was evaporated to dryness and then dissolved in dichloromethane and washed with saturated aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. The residue was recrystallised from methanol/ethyl acetate to give, as a solid 1-(4-bromophenylsulphonyl)4-[1-(6-methylaminopyrimidin-4-yl)-piperazin-4-ylcarbonyl]piperazine (0.65 g), mp 219-221° C. Found C, 45.80; H, 5.10 and N, 18.50%. C20H26BrN7O3S requires C, 45.80; H, 5.00 and N, 18.70% NMR (CDCl3): 2.85 (d, 3H), 3.00 (m, 4H), 3.30 (m, 4H), 3.40 (m, 4H), 3.60 (m, 4H). 4.75 (m, 1H), 5.40 (s, 1H), 7.60 (d, 2H), 7.70 (d, 2H) and 8.15 (s, 1H); m/z 524 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@H:10]1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg+].[Br-].[CH3:33]C(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:33])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[S:14]2)[C@H:10]1[F:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2[C@@H](F)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.930 g, 2.19 mmol) in anhydrous THF (15 mL), at 0° C. and under N2, was added MeMgBr (1.4 M in THF/toluene, 3.0 mL, 5.2 mmol). After addition the mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated aqueous NaHCO3 solution (30 mL), and then extracted with EtOAc (3×30 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was dissolved in DCM (40 mL) and Boc2O (2.0 g, 9.2 mmol) was added. The mixture was stirred at room temperature for 16 h. After concentration the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording tert-butyl ((3aR,5R,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as an off-white foam (0.767 g, 80%), which contained two diastereomers.