Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.[CH3:38][O:39][C:40](=[O:50])[C:41]1[CH:46]=[CH:45][C:44]([C:47](Cl)=[O:48])=[CH:43][CH:42]=1>CN(C=O)C>[CH3:38][O:39][C:40](=[O:50])[C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:10]3[C:5]([O:4][C:3]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=4[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=3)=[O:12])[CH2:14][CH2:15]2)=[O:48])=[CH:43][CH:42]=1
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)N2CCN(C(=O)c3cc(F)cnc3Oc3cc(Cl)ccc3Cl)c3ccccc32)cc1
Temperature: 120 °C
Yield: 10.8 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (52.3 mg, 0.125 mmol, 1.0 equiv; Example 147) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (65 mg, 85 μL, 0.5 mmol, 4.0 equiv; [CAS RN 7087-68-5]) and 4-chlorocarbonyl-benzoic acid methyl ester (29.8 mg, 0.15 mmol, 1.2 equiv; [CAS RN 7377-26-6]). The reaction mixture was heated by microwave irradiation to 120° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 7.8 mg (11%) of the title compound as a white powder. MS (ISP): 580.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[C:3]#[N:4].B.C1COCC1>C1COCC1>[CH3:5][C:2]([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: CC(C)(C#N)Sc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(CN)Sc1ccccc1
Reaction time: 18 h

Procedure:
A solution of Example 266A (0.5 g, 2.82 mmol) in THF at room temperature was treated with 1M BH3.THF (15 mL), stirred for 18 hours, quenched with methanol (5 mL), and concentrated. The concentrate was treated with 2M HCl (50 mL) and concentrated. The the organic phase was dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI(+)) m/e 182 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16][O:17]C(=O)C)[N:6]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16][OH:17])[N:6]2[CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(=O)OCc1nc2c(Cl)ncnc2n1CC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Cn1c(CO)nc2c(Cl)ncnc21

Procedure:
A solution of 6-chloro-8-acetoxymethyl-N9-neopentylpurine (1 mmol) in THF-water was treated with aqueous sodium hydroxide (1.5 mmol) at 0° C. for 0.5 h. Extraction and chromatography afforded 6-chloro-8-hydroxymethyl-N9-neopentylpurine as a yellow gel. TLC: Rf=0.38, 33% EtOAc-hexane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:16][CH2:17][O:18][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (0.4300 g, 1.02 mmol), 4-dimethylaminopyridine (0.0783 g, 0.64 mmol), triethylamine (0.8 mL, 5.74 mmol), and tert-butyldimethylsilyl chloride (0.2870 g, 1.90 mmol) in CH2Cl2 was stirred for 16 h at rt. After the solvents were removed in vacuo, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to give 0.2856 g of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one as a solid. LC-MS Method 1 tR=2.49 min, m/z 560, 558 (MNa+), 538, 536 (MH+), 494, 492; 1H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 4H), 7.10-7.05 (m, 2H), 6.78 (d, J=8.5 Hz, 2H), 5.63 (q, J=7.0 Hz, 1H), 3.84-3.78 (m, 1H), 3.44-3.38 (m, 1H), 2.96-2.90 (m, 1H), 2.78-2.27 (m, 3H), 2.18-2.04 (m, 2H), 1.52 (d, J=7.3 Hz, 3H), 0.87 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −114.99 (m).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]1([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]2[CH:27](N)C)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:27][C:19]3[N:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(N)c1nc2ccccc2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ncnc2c1c(I)cn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.15 g, 4.1 mmol), 1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (1.0 g, 4.1 mol) and K2CO3 (0.6 g, 4.3 mmol) in DMSO (20 mL) was stirred at room temperature overnight. Then the mixture was added H2O (50 mL) and extracted with CH2Cl2 (20 mL×3). The combined organic layers were concentrated in vacuo to give 4-chloro-5-iodo-7-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.7 g, yield 85%) as brown solid.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[CH3:27][O-:28].[Na+]>>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][O:28][CH3:27])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: C[O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: [Na+]
Product: COCc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (50 mg) was added to a freshly prepared sodium methoxide solution (0.08M, 12 ml), and the reaction stirred at room temperature for 96 hours. The reaction was partitioned between ethyl acetate and water, the organic phase dried (sodium sulphate) and reduced to dryness under vacuum. The residue was applied to a bond-elut (silica, 5 g) and eluted with an ethyl acetate/cyclohexane gradient. The product fractions were reduced to dryness under vacuum and further purified by HPLC, to give after evaporation of the solvent, N-cyclopropyl-4′-[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:19][NH2:20]>C(O)C>[C:1]1([C:7]2[NH:20][N:19]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(=O)c1ccccn1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cc(-c3ccccn3)n[nH]2)cc1
Yield: 97.6 %

Procedure:
A 250 mL flask was charged with compound (1) (10 g 44 mmol), a magnetic follower and 150 mL of ethanol. Hydrazine monohydrate (2.15 mL, 44 mmol) was added and the mixture refluxed overnight. On cooling the ethanol was removed and the residue recrystallised from methanol to yield 2-(5-phenylpyrazol-3-yl)pyridine (2) as a pale yellow crystalline solid (9.5 g, 97%).
Reaction SMILES: [BH4-].[K+].[CH3:3][C:4]1([CH3:21])[NH:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[O:5]1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][CH:29]([Cl:33])[C:30](Cl)=[O:31]>O>[Cl:28][CH:29]([Cl:33])[C:30]([N:8]1[C@H:7]([CH2:9][OH:10])[C@@H:6]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[O:5][C:4]1([CH3:21])[CH3:3])=[O:31]
Reactant: CC1(C)N[C@H](CO)[C@@H](c2ccc(S(C)(=O)=O)cc2)O1
Reactant: O=C(Cl)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: O
Product: CC1(C)O[C@H](c2ccc(S(C)(=O)=O)cc2)[C@@H](CO)N1C(=O)C(Cl)Cl
Temperature: 55 °C
Reaction time: 6 h

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound IV) (100 g, 0.3480 moles) in 500 mL of methanol reacts with 2,2-dimethoxypropane (39.9 g, 0.3828 moles) and lithium carbonate at 60-70° C. to yield (4S,5R)-2,2-dimethyl-4-ethylcarboxyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound XIVa) (113.9 g, 0.3480 moles). Addition of potassium borohydride (28.2 g, 0.5220 moles) with stirring over 4-8 hours at 50-60° C. then yields (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound VIIIa). Addition of potassium carbonate (19.0 g, 0.1914 moles) and dichloroacetyl chloride (56.4 g, 0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (500 mL) precipitates the crude product. Filtration, washing with water (250 mL) then drying yields (4R,5R)-3-dichloroacetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound XIIa).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH3:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[CH2:26][S:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C>C(O)C>[CH3:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[CH2:26][S:27][CH2:28][CH2:29][NH:30][C:5]1[C:4]2[N:8]=[CH:9][N:10]([C:3]=2[N:2]=[CH:1][N:6]=1)[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1CSCCNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
5.0 g of 6-chloropurine riboside (0.0179 moles) 4.6 g of 4-methyl-5-[(2 aminoethyl)-thiomethyl]-imidazole (0.019 moles), and 8.78 ml of triethylamine (0.063 moles) are refluxed overnight in 100 ml of ethanol. 15 ml of solvent are then removed with nitrogen gas. The crystals formed therefrom are filtered and washed with ethanol. The crystals are then recrystallized from ethanol and washed with diethyl ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Li])CCC.[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.Cl>O1CCCC1.CCCCCC>[O:14]1[CH2:15][CH:16]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:18][CH2:19]1
Reactant: O=C1CCOCC1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1ccc(C2=CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[lacuna] is added at −40° C. to 12.7 g of 4-bromophenol in 150 ml of tetrahydrofuran. At this same temperature, 100 ml of 1.6 M butyllithium in hexane are added to the reaction mixture, followed by addition of 8.1 g of 4-tetrahydropyranone. The reaction mixture is left stirring for 18 hours at room temperature and then hydrolysed with 1 N hydrochloric acid. The resulting mixture is extracted several times with diethyl ether, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The solid obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate mixture varying from 90/10 to 80/20 (v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=O.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]1[CH:6]=[C:7]([NH2:8])[NH:14][N:15]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccccc1Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2Cl)n[nH]1
Temperature: 25 °C

Procedure:
A solution of 2-chlorobenzoylacetonitrile (15.9 g, 89 mmol) and hydrazine hydrate (8.9 g, 0.18 mol) in ethanol (2 ml) was heated at reflux for 22 hr. After cooling to room temperature, the reaction was concentrated, in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated, in vacuo, to a brown oil. Flash chromatography using 10% ethyl acetate in methylene chloride, changing to 5% methanol in methylene chloride as eluant afforded title product I-1A-1a (17.3 g, quantitative): +ESI MS (M+1) 194.2; 1H NMR (400 MHz, CD3OD) δ 7.60–7.25 (m, 4H), 5.99 (br s, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:28][CH2:27][S:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OO)=[O:32].OO>C(O)(C(F)(F)F)=O.C(Cl)Cl.[OH-].[Na+]>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:24][CH2:25][S:26](=[O:32])[CH2:27][CH2:28]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)C(F)(F)F
Reactant: c1cc(C2(CN3CCSCC3)CCOCC2)ccc1OCCCN1CCCC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 4-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-thiomorpholine (200 mg, 0.494 mmol) in TFA (0.67 ml) at 5 to 10° C. was added dropwise a solution of trifluoro-peracetic acid [4M solution prepared by the addition of 27.5% H2O2 (0.94 ml) to TFA (1.56 ml)] and stirred at 5 to 10° C. for 1 hour. The reaction mixture was diluted with DCM (5 ml) and NaOH (5M solution, 4 ml) was added to attain pH14. The mixture was extracted with DCM ((2×5 ml), the combined DCM extracts were washed with saturated aqueous brine (10 ml), dried over MgSO4, filtered and concentrated in vacuo. The isolated yellow oil was purified by column chromatography on silica eluting with DCM(95):MeOH(4):NH3(I) to give the title compound as a yellow oil (165 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.87 (d, 2H), 4.02 (t, 2H), 3.81-3.69 (m, 2H), 3.59-3.43 (m, 2H), 2.99-2.82 (m, 2H), 2.76-2.2.59 (m, 6H), 2.53 (br s, 4H), 2.46 (s, 2H), 2.31-1.73 (m, 12H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCOCCOCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCOCCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Triphenylphosphine (6.55 g) in dichloromethane (30 ml) was added dropwise to 3-[2-(4-phenylbutoxy)ethoxy]-1-propanol (5.0 g) and carbon tetrabromide (8.3 g) in dichloromethane (30 ml) at 0°. The mixture was stirred at room temperature for 1 h, evaporated onto silica, and purified by FCC eluting with cyclohexane - followed by System B (1:9) to give the title compound (5.4 g) as an oil. T.l.c. (System B 1:9) Rf 0.35
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][CH2:26][O:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][CH2:26][O:25]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCOC(CON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCOC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.22 g, 0.80 mmol) in dry DCM (20 mL) were added tert-butyl 2-[(aminooxy)methyl]-1,4-oxazepane-4-carboxylate 131 (0.23 g, 0.93 mmol, US 2010/0168080 and J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.15 g, 1.12 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.12 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 2-{[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}-1,4-oxazepane-4-carboxylate 132 (0.32 g, 80%) as a clear thick oil.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].CCN(C(C)C)C(C)C.[N:14]([CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O-:20])=[O:19])=[N+:15]=[N-:16]>>[N:14]([C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([O:20][CH2:2][C:3]#[N:4])=[O:19])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=NC(Cc1ccccc1)C(=O)[O-]
Reactant: N#CCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCOC(=O)[C@H](Cc1ccccc1)N=[N+]=[N-]
Reaction time: 12 h
Yield: 50 %

Procedure:
Chloroacetonitrile (1 mL) and DIPEA (310 mg, 0.411 mL, 2.41 mmol) were added to 2-azido-3-phenylpropanoate and stirred for 12 h. The solvent was removed under reduced pressure and SiO2 flash chromatography (40-50% ethyl acetate in hexanes) afforded (250 mg) of a white solid in 50% yield. Rf 0.5 in 50% ethyl acetate in hexanes; 1H NMR (500 MHz, CDCl3) δ 7.37 (t, J=7.6 Hz, 2H), 7.32-7.29 (m, 1H), 7.25 (t, J=7.6 Hz, 2H), 4.77 (t, J=1.0 Hz, 1H), 4.18 (dd, J=6.2, 1.8 Hz, 1H), 3.21 (dd, J=14.0, 5.8 Hz, 1H), 3.08 (dd, J=13.9, 8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 168.8, 135.1, 129.3, 129.1, 127.8, 113.7, 62.9, 49.3, 37.7; HRMS (ESI) m/z calcd for C11H10N4O2Na [M+Na]+ 253.070. found 253.071.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:31]([C@:33]([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][NH2:45])[OH:43])[OH:41])[OH:39])([OH:37])[C:34]([OH:36])=[O:35])=[O:32])[CH2:24][S:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])=[O:21])[CH2:10][CH:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:12](=[O:14])[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:61][Si:62]([CH:65](O)[CH3:66])([CH3:64])[CH3:63]>CN(C)C=O>[CH3:61][Si:62]([CH2:65][CH2:66][O:35][C:34]([C@@:33]([C:31](=[O:32])[C@H:23]([CH2:24][S:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[NH:22][C:20](=[O:21])[C@H:9]([CH2:10][CH:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:12](=[O:13])[OH:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][NH2:45])[OH:43])[OH:41])[OH:39])[OH:37])=[O:36])([CH3:64])[CH3:63]
Reactant: CC(O)[Si](C)(C)C
Reactant: CC(=O)NCSC[C@H](NC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)C(=O)[C@](O)(C(=O)O)[C@@H](O)[C@H](O)[C@H](O)CN
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)NCSC[C@H](NC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)C(=O)[C@](O)(C(=O)OCC[Si](C)(C)C)[C@@H](O)[C@H](O)[C@H](O)CN
Reaction time: 0.33 h

Procedure:
To 5 mL of a solution containing 1 mmol of the above acid 5, anhydrous dimethylformamide, and 1 mmol of N-methylmorpholine maintained at 0°-5° C., 1 mmol of isobutylchloroformate is added, and the mixture is kept at this temperature for 20 minutes. To this solution is added a solution of 1 mmol of trimethylsilylethanol in 2 mL of anhydrous dimethylformamide (previously cooled to 0°-5° C.), and the solution is stirred for 1 hour at this temperature and allowed to come to room temperature. The solvent is removed in vacuo and the residue is dissolved in 20 mL of ethyl acetate and washed with water. The organic layer is dried and evaporated to give 6.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[N:4]1)[CH3:2].[NH2:15][C@H:16]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:19]([CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:18][CH2:17]1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH:15][C@H:16]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C@@H:19]([CH2:29][C:30]3([OH:36])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[CH2:18][CH2:17]2)=[O:14])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(=O)O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@@H]1CC1(O)CCOCC1
Product: CCn1nc(C(=O)N[C@@H]2CC[C@H](CC3(O)CCOCC3)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 2 from 1-ethyl-1H-indazole-3-carboxylic acid (Chemical & Pharmaceutical Bulletin, 1995, 43, 1912-1930) and (+)-tert-butyl cis-5-amino-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (step 1 of Example 27).
Reaction SMILES: [Cl-].[C:2]([NH:6][S:7]([C:10]1[CH:15]=[C:14]([CH2:16][NH:17][CH3:18])[CH:13]=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:21])=[O:20])(=[O:9])=[O:8])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C>ClCCl>[C:2]([NH:6][S:7]([C:10]1[CH:15]=[C:14]([CH2:16][N:17]([CH3:18])[S:7]([CH3:10])(=[O:9])=[O:8])[CH:13]=[CH:12][C:11]=1[S:19]([CH3:22])(=[O:21])=[O:20])(=[O:8])=[O:9])([CH3:5])([CH3:4])[CH3:3]
Reactant: CNCc1ccc(S(C)(=O)=O)c(S(=O)(=O)NC(C)(C)C)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccc(S(C)(=O)=O)c(S(=O)(=O)NC(C)(C)C)c1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 179.4 %

Procedure:
0.39 ml (5 mmol) of methenesulfonyl chloride dissolved in 5 ml of dichloromethane are added dropwise to a solution of 1.67 g (5 mmol) of N-tert-butyl-5-methylaminomethyl-2-methanesulfonylbenzenesulfonamide and 0.73 ml (5.3 mmol) of triethylamine in 20 ml of dichloromethane which had been cooled to 0° C. After 30 min at room temperature, the reaction solution is washed with water, dried and completely evaporated in vacuo. 1.85 g (89.7%) of N-tert-butyl-5-(N-methyl-N-methanesulfonylaminomethyl)-2-methanesulfonylbenzenesulfonamide are obtained as a viscous oil.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][OH:12])(=[O:8])=[O:7])C.Cl[C:18]1[C:19]([CH3:28])=[CH:20][C:21]2[N:22]([N:24]=[C:25]([CH3:27])[N:26]=2)[N:23]=1>>[CH2:15]([C:10]([CH2:13][CH3:14])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:18]1[C:19]([CH3:28])=[CH:20][C:21]2[N:22]([N:24]=[C:25]([CH3:27])[N:26]=2)[N:23]=1)[CH3:16]
Reactant: CCC(CC)(CO)CS(=O)(=O)N=CN(C)C
Reactant: Cc1nc2cc(C)c(Cl)nn2n1
Product: CCC(CC)(COc1nn2nc(C)nc2cc1C)CS(N)(=O)=O

Procedure:
Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-propanol and 6-chloro-2,7-dimethyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 221°-222° C.