Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C[Si]([N:29]=[C:30]=[O:31])(C)C>C1COCC1>[C:30]([NH:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)(=[O:31])[NH2:29]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNC(N)=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 114.8 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (125 mg) in THF (1.5 mL) was added trimethylsilyl isocyanate (57.7 mg), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (160 mg).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[F:9][C:10]([F:27])([F:26])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[CH:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[N:12]=1>CC(C)=O>[CH3:3][O:21][C:15]1[CH:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[N:12]=[C:11]([C:10]([F:26])([F:9])[F:27])[C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(OC)cc(C(F)(F)F)nc1C(F)(F)F

Procedure:
A mixture of methyl iodide (32.3 ml, 0.519 mol), potassium carbonate (14.4 g, 0.104 mol), and product of Step 2 (25.0 g, 0.086, 5 mol) in acetone (100 ml) was refluxed for 18 hours and concentrated. The residue was dissolved in ether and washed with water. The ether layer was worked up as usual. The crude product, a yellow solid (27.25 g), was recrystallized (chloroform petroleum ether) to afford white rods (22.95 g), yield--88%; mp 101°-103° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[C:11]([C:15]1([CH2:19]O)[CH2:18][O:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]12[CH2:16][O:17][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8])([O:10][CH2:19]1)[O:9][CH2:18]2)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C1(CO)COC1
Reactant: C#CCCCCCC(=O)O
Product: C#CCCCCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-(hept-6-ynyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from oct-7-ynoic acid and 3-t-butyl-3-hydroxymethyloxetane using methodology described in Example I.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35](Cl)=[O:36]>C1COCC1>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:35]([C:25]3[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:27][O:28][C:24]=3[CH3:23])=[O:36])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 489.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)=[O:18]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)C(Cl)(Cl)Cl)CC1
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 1-(2-methoxyphenyl) piperazine (7.0 g) in dichloromethane (30 ml) was added over 0.25 h to a stirred solution of trichloroacetyl chloride (4.06 ml) in dichloromethane (40 ml) at room temperature under argon. Diisopropylethylamine (5.95 ml) was then added and the whole was stirred for 18 h. The reaction mixture was washed with water (2×100 ml), dried (Na2SO4) and concentrated to give the title compound (D3) as an oil (11.2 g, 91%). MH+337/339.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Br.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:13]1[CH:12]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Cu]Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
In a 500 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.07 g (0.0005 mol (corresponding to 1% by mol)) of copper(I) bromide and 50 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 14.0 g (0.060 mol) of 2-bromobiphenyl and 1.7 g (0.072 mol) of metallic magnesium in 100 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 30° C. to 35° C. After the dropwise addition was completed, stirring was conducted at a reflux temperature for 4 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 30 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain coarse crystals. The coarse crystals were recrystallized from MeOH to obtain 13.2 g (purity: 99.0%) of the aimed di-tert-butyl(2-phenylphenyl)phosphine. The yield was 87.5%. Melting point: 84-85° C.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:17][CH2:18][CH2:19][SH:20])C=CC=CC=1>>[CH:1]1([NH:7][C:8]([S:20][CH2:19][CH2:18][NH2:17])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: S=C=NC1CCCCC1
Product: NCCSC(=S)NC1CCCCC1

Procedure:
Cyclohexylisothiocyanate (0.2 ml) and N-triphenylmethylcysteamine (150 mg) were subjected to the reaction described in Reference 5. From the reaction product, triphenylmethyl was removed by the method described in Reference 4 to obtain 2-cyclohexylaminothiocarbonylthioethylamine (crude formate: 92 mg). The product was dissolved in anhydrous methanol (2 ml). Triethylamine (0.24 ml) and mitomycin A (97 mg: 0.8 molar equivalent) were added to the reaction solution which was then treated in a similar manner to that described in Example 1 to obtain Compound 37 (54 mg) in the form of grayish blue powders with a yield of 36%.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:28][CH2:29][CH2:30][Cl:31]>CN(C=O)C>[Cl:31][CH2:30][CH2:29][CH2:28][N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][C:10]([S:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)[CH2:17]1
Reactant: ClCCCBr
Reactant: O=S(=O)(c1ccc2c(c1)CNCC2)N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc2c(c1)CN(CCCCl)CC2)N1CCOCC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
1.2 g (4.4 mmol) of 7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetra-hydroisoquinoline and 1.0 g (10 mmol) of triethylamine were dissolved in DMF at 40° C., 1.1 g (6.6 mmol) of 1-bromo-3-chloropropane were added dropwise, and the mixture was stirred at 40° C. for 3 h. For workup, the mixture was concentrated, and the residue was taken up in water and extracted with methyl tert-butyl ether. Drying over sodium sulfate, filtration and removal of the solvent were followed by purification by chromatography (silica gel; mobile phase: methylene chloride with 2% methanol) to afford 0.7 g (2 mmol) of a pale oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[I:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[I:30])[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1C[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1C[C@H](n2c(I)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 39.6 %

Procedure:
(±)(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 1.13 mmol) was dissolved in dry N,N-dimethylformamide (4 mL) and heated to 95°-105° C. N-Iodosuccinimide (534 mg, 2.3 mmol as 95%) was added in portions over 5.5 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Elution with 10% ethyl acetate-hexanes followed by solidification from ethanol-water gave (±)(1R*,2S*,3S*,5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate as a white powder (255 mg, 40%), m.p.152.5°-153° C.; 1H-NMR(DMSO-d6) δ: 8.32 and 7.94 (both s, 2,2 aromatic CH), 5.8-5.7 (m, 1, OCH), 5.4-5.3(m, 1, OCH), 5.2-5.0 (m, 1, NCH), 4.35-4.2 (m, 2, OCH2), 2.7-2.6 (m, 1, CH), 2.35-2.25 (m, 2, CH2), 2.11, 2.08, and 1.93 (all s, 3 each, 3 CH3); mass spectrum(CI) 569 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[CH:58][C:57]=1[C:61](Cl)=[O:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:57]2[CH:58]=[N:59][O:60][C:56]=2[CH3:55])=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1oncc1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1oncc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-methylisoxazole-4-carbonyl chloride as starting materials in 44% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.05 (s, 1H), 9.41 (s, 2H), 9.02 (s, 1H), 8.65 (s, 1H), 8.33 (s, 2H), 8.20 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.42 (m, 1H), 3.70 (m, 1H), 3.12 (m, 2H), 2.98 (m, 4H), 2.49 (s, 3H), 2.30 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C29H30ClN8O3 (M+H)+: m/z=573.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][CH2:14][NH:15][C:16]([O:18]C(C)(C)C)=O)=[C:6]([CH:11]=1)C(OC)=O.C(O)(C(F)(F)F)=O.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][CH2:13][CH2:14][NH:15][C:16](=[O:18])[C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc(Br)ccc1OCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCOc2ccc(Br)cc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 58.9 %

Procedure:
A solution of methyl 5-bromo-2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]oxy}benzoate (Preparation 70) (8.92 g, 23.8 mmmol) in DCM (18 ml) was treated with TFA (7 ml) and stirred for 5 hrs. Additional (2 ml) TFA was added and the reaction left overnight. The solvent was evaporated, re-evaporated with toluene (5×) and dissolved in toluene (50 ml). The resulting residue was treated with triethylamine (4 equiv) and heated at 100° C. overnight then evaporated. The residue was purified by flash chromatography twice eluting with 50% EtOAc/hexane then 40-45% EtOAc/hexane. The fractions were evaporated to give the title compound (3.4 g) as a white solid. MS (ES): C9H881BrNO2 requires 243; found 244 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:12][C@@H:13]1[N:18]([C:19]2[N:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[Cl:56][C:57]1[N:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1>C(Cl)Cl>[Cl:56][C:57]1[N:62]=[CH:61][C:60]([S:63]([N:15]2[CH2:16][CH2:17][N:18]([C:19]3[N:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:28])([F:29])[F:27])[C:30]([F:33])([F:31])[F:32])=[CH:23][N:24]=3)[C@@H:13]([CH2:12][N:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]2)(=[O:65])=[O:64])=[CH:59][CH:58]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CN(c2ccccc2)S(C)(=O)=O)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 55.9 %

Procedure:
A 5-mL vial was charged with (R)-tert-butyl 4-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyrimidin-2-yl)-3-((N-phenylmethylsulfonamido)methyl)piperazine-1-carboxylate (0.214 g, 0.348 mmol, Example 233, Step 5), TFA (1.0 mL, 13 mmol) and CH2Cl2 (2 mL). The mixture was stirred at room temperature for 35 min and then concentrated. CH2Cl2 (2 mL) and triethylamine (0.50 mL, 3.6 mmol) were added and the mixture was stirred at room temperature for 10 min. 6-chloropyridine-3-sulfonyl chloride (0.0910 g, 0.429 mmol, Organic Process Research & Development 2009, 13, 875) was then added in potions and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated and purified by column chromatography (50 g of silica gel, 0 to 60% EtOAc in hexanes) to afford N-(((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.134 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@H:16]([O:17][S:45]([C:42]2[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=2)(=[O:47])=[O:46])[C@@H:15]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](OS(=O)(=O)c2ccc(C)cc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Methyl 3-O-benzyl-6-O-trityl-2-deoxy-α-D-ribo-hexopyranoside (13.3 g; 26.05 mmoles) was dissolved in dry pyridine (41 ml) and cooled in an ice bath under nitrogen. p-Toluenesulfonyl chloride (9.93 g, 52.09 mmoles) was added all at once and the reaction was stirred at room temperature under nitrogen overnight. The reaction was partitioned between ether and water. The ether layer was extracted four times with water, dried (K2CO3, anhyd), and the solvent evaporated in vacuo to leave 19.1 g of crude product which was chromatographed on silica gel (1 kg) eluting with methylene chloride until excess p-toluenesulfonyl chloride had been eluted. Elution was continued with 2% (by volume) acetone in methylene chloride. Fractions containing the product were collected and evaporated to dryness to leave 15.5 g of methyl 3-O-benzyl-4-O-tosyl-6-O-trityl-2-deoxy-α-D-ribo-hexopyranoside as a glassy gum, [α]D25 =66.24 (C, 1.0, CHCL3)
Reaction SMILES: [C:1]([C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([F:12])[N:4]=1)#[N:2].N.[OH:14]S(O)(=O)=O>>[F:12][C:5]1[N:4]=[C:3]([C:1]([NH2:2])=[O:14])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nc(F)ccc1[N+](=O)[O-]
Agent: N
Product: NC(=O)c1nc(F)ccc1[N+](=O)[O-]
Yield: 61 %

Procedure:
A solution of 2-cyano-6-fluoro-3-nitropyridine (1.40 g, 8.39 mmol) in 90% H2SO4 (30 mL) is warmed at 70° C. for 90 min, then cooled, poured onto ice and basified with conc. ammonia. Extraction with EtOAc and workup gives 6-fluoro-3-nitropyridine-2-carboxamide (0.94 g, 61%). 1H NMR (CDCl3) δ 8.70 (1H, dd, J=8.9, 6.5 Hz), 8.30, 8.03 (1H, 1H, brs), 7.62 (1H, dd, J=8.9, 2.9 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.[N:37]1([C:45](=O)[CH2:46]Cl)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH2:45][CH2:46][O:1][C:2]2[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[CH:18]3[CH2:27][CH2:26][C:25]4[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=4[CH2:19]3)=[CH:4][CH:3]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CCCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCCCCC3)cc2)c1
Yield: 12.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-azocan-1-yl-2-chloroethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.5 mg) was obtained.
Reaction SMILES: BrC1CCCC1.BrCC1CC1.[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:46])[C@H:21]([NH:25][C:26]([C:28]2[C:36]3[C:31](=[N:32][CH:33]=[C:34](Br)[N:35]=3)[N:30](COCC[Si](C)(C)C)[CH:29]=2)=[O:27])[CH:22]2[CH2:24][CH2:23]2)[CH2:16][CH2:15]1)#[N:13].C([CH:49]1[CH2:54][CH2:53][N:52]([C:55]([C@H:57]([NH:62][C:63](C2C3N=C(Br)C=NC=3N(COCC[Si](C)(C)C)C=2)=O)C(C)(C)C)=O)[CH2:51][CH2:50]1)#N>>[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:46])[C@H:21]([NH:25][C:26]([C:28]2[C:36]3[C:31](=[N:32][CH:33]=[C:34]([C:57]4[N:62]=[CH:63][N:52]([CH:51]5[CH2:50][CH2:49][CH2:54][CH2:53]5)[CH:55]=4)[N:35]=3)[NH:30][CH:29]=2)=[O:27])[CH:22]2[CH2:23][CH2:24]2)[CH2:16][CH2:15]1)#[N:13]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Agent: BrC1CCCC1
Agent: BrCC1CC1
Product: N#CC1CCN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4cn(C5CCCC5)cn4)nc23)C2CC2)CC1

Procedure:
Prepared according to the procedure outlined in Example 131 substituting bromocyclopentane for (bromomethyl)cyclopropane in Step 1 and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide in Step 3. MS: (M+H)+=487.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:9][C:6]=2[C:7]#[N:8])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: Cc1ccc(-n2cnc(C)c2)c(C#N)c1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cnc(C)c2CN(C)C)c(C#N)c1
Yield: 64 %

Procedure:
In analogy to example 5b, 5-methyl-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 4 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as an oil that solidifies on standing (yield: 64%). MS: m/e=255.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C1(N[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([O:14][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reaction time: 0.5 h

Procedure:
A solution of t-butyl-4-oxopiperidine-1-carboxylate (6.50 g, 32.6 mmol) in THF (50 mL) was added dropwise to a stirred solution of LDA (24 mL, 35.8 mmol, 1.1 eq., 1.5 M in hexanes) in THF (50 mL) at −78° C. After stirring for 30 min, a solution of N-phenyltrifluoromethanesulfonamide (12.48 g, 35.0 mmol, 1.07 eq.) in THF was added. The reaction mixture was stirred under inert atmosphere for 6 h at 0° C. The reaction was concentrated in vacuo and filtered over a pad of alumina (hexanes/EtOAc 9:1) to afford 2 as a pale yellow oil which was used without further purification (10.26 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][N:8]=2)[S:5][CH:6]=1.C(#N)C.CC(O)=O.C1C(=O)N([Br:27])C(=O)C1>O>[Br:27][C:6]1[S:5][C:4]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][N:8]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: Cn1ncnc1-c1cc(Cl)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: Cn1ncnc1-c1cc(Cl)c(Br)s1
Yield: 83.8 %

Procedure:
A 3-L reaction flask equipped with a cooling bath, air stirrer, and thermometer probe is charged with 5-(4-Chloro-thiophen-2-yl)-1-methyl-1H-[1,2,4]triazole (105.3 g, 0.527 moles), ACN (1053 mL) and HOAc (105 mL) to form a solution. NBS (103.2 g, 0.580 moles) is added portion-wise over 30-60 minutes while maintaining the temperature at ≦31° C. After stirring for 1 hour2, GC analysis indicated reaction completion. The reaction mixture is poured into de-ionized H2O (2.1 L, 20 vol), stirred for 30 minutes, filtered, and washed with de-ionized H2O (2×1 L). The product is dried in a vacuum oven at 45° C. overnight to give the title compound as a pale yellow solid (123.0 g, 83.8%; 96.6% area-% by GC). 2 The reaction temperature decreased after 1 hour to 26.7° C.