Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=O)=[CH:24][CH:23]=1.[OH-].[Na+]>>[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([CH2:26][NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:31][CH:30]=2)=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(NCc3ccc(Cl)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-chloro-N-(4-hydroxyphenyl)benzamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H26ClNO6 [M+H]+: 484.
Reaction SMILES: I[C:2]1[C:3]2[C:26]3=[CH:27][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]4[O:37][C:14]([NH:15][C@@H:16]([CH:34]([CH3:36])[CH3:35])[C:17](=[O:33])[N:18]5[CH2:28][C@H:21]([O:22][C:23]3=[N:24][CH:25]=1)[CH2:20][C@H:19]5[C:29]([O:31][CH3:32])=[O:30])=[N:13][N:12]=4)=[CH:5][CH:4]=2.[CH2:38]([Sn](CCCC)(CCCC)C=C)[CH2:39]CC>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH:34]([C@@H:16]1[NH:15][C:14]2[O:37][C:11](=[N:12][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2[CH:27]=[C:26]3[C:3](=[CH:4][CH:5]=2)[C:2]([CH:38]=[CH2:39])=[CH:25][N:24]=[C:23]3[O:22][C@H:21]2[CH2:28][N:18]([C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:20]2)[C:17]1=[O:33])([CH3:36])[CH3:35]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)C)Nc1nnc(o1)CCCCc1ccc3c(I)cnc(c3c1)O2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1cnc2c3cc(ccc13)CCCCc1nnc(o1)N[C@@H](C(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)OC)O2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a 0.1 M solution of methyl (3R,5S,8S)-22-iodo-8-isopropyl-7-oxo-2,27-dioxa-6,9,11,12,24-pentaazapentacyclo[16.6.2.13,6.110,13.021,25]octacosa-1(24), 10,12,18,20,22,25-heptaene-5-carboxylate (Example 12, Step 2) in dry toluene was added tetrakis(triphenylphosphine)palladium(0) (0.05 eq.). N2 was bubbled through the reaction mixture for 5 minutes and tributylethenylstannane (1.5 eq) was added. The mixture was stirred at 100° C. for 1 h, allowed to cool to RT, diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (20% to 40% EtOAc/PE) to give the compound as a white solid. MS (ES+) C28H33N5O5 requires: 519. Found: 520 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].Cl.[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=3)=[O:4])[CH2:23][CH2:24]2)=[N:26]1
Reactant: CC(=O)Nc1ccc(C(=O)CCl)cc1C(C)C
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: CC(=O)Nc1ccc(C(=O)CN2CCN(c3nsc4ccccc34)CC2)cc1C(C)C
Yield: 55.1 %

Procedure:
Starting with N-[4-(2-Chloro-acetyl)-2-isopropyl-phenyl]-acetamide (0.380 g, 1.498 mmole), and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.383 g, 1.498 mmole, 1.0 eq) and following the procedure as outlined in Example 17, N-{4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-acetyl]-2-isopropyl-phenyl}-acetamide (0.360 g, 0.825 mmole) was obtained as its hydrochloride salt from treatment with dioxane/HCl(gas).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][P:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][C:32]([CH3:55])=[CH:33][CH2:34][C:35]1[C:43]([O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])=[C:42]2[C:38]([CH2:39][O:40][C:41]2=[O:51])=[C:37]([CH3:52])[C:36]=1[O:53][CH3:54].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([P:5]([O:7][CH2:8][C:9]([F:12])([F:10])[F:11])([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[O:6])[CH2:31][C:32]([CH3:55])=[CH:33][CH2:34][C:35]1[C:43]([O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:48])[CH3:49])=[C:42]2[C:38](=[C:37]([CH3:52])[C:36]=1[O:53][CH3:54])[CH2:39][O:40][C:41]2=[O:51]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CBr)C(=O)OC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)P(=O)(OCC(F)(F)F)OCC(F)(F)F
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (186 μL, 0.88 mmol) in anhydrous THF (2 mL) was added a solution of 1N NaN(TMS)2 in THF (0.88 mL, 0.88 mmol). The solution was stirred at room temperature for 30 minutes, whereupon a solution of 6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (98 mg, 0.22 mmol) in THF (1 mL) was added. The reaction mixture was stirred overnight when a precipitate was observed. The reaction mixture was worked up by addition of a saturated aqueous solution of ammonium chloride and extraction of the product with EtOAc. The organic extract was dried and the product was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 72 mg (48%) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.22 (t, 3H, J=7 Hz), 1.81 (s, 3H), 2.18 (s, 3H), 2.5-2.7 (m, 2H), 3.3 (ddd, 1H, J=4, 12, 23 Hz), 3.40 (d, 2H, J=7 Hz), 3.65 (s, 3H), 3.76 (s, 3H), 4.29-5.13 (m, 6H), 5.13 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm; MS (m/z) 701.2 [M+Na]+.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8]C)=O.[CH3:13][C:14](=[O:22])[CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO>[CH2:17]([CH:16]1[CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([OH:8])=[CH:13][C:14](=[O:22])[CH2:15]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC=CC(C)=O
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC1CC(=O)C=C(O)C1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a stirring solution of sodium methoxide (32.4 g, 0.60 mol) and dimethyl malonate (90 g, 0.68 mol) in 230 mL of anhydrous methanol was added portion wise 75 g (0.48 mol) of 90% 3-nonen-2-one. The reaction mixture was then refluxed for 3 h under N2 and allowed to cool to room temperature. The solvent was distilled under reduced pressure and the residue dissolved in 350 mL of water. The slurry of white crystals and the almost clear solution was extracted thrice with 80 mL of chloroform. The aqueous layer was acidified to pH 4 with concentrated HCl and the white precipitate that formed was allowed to stand overnight prior to filtration. The crystals were dried at 50° C. under high vacuum for 5 hours to yield 106.5 g (0.4416 mol) (92%) of methyl 6-n-Pentyl-2-hydroxy-4-oxo-cyclohex-2-ene-1-carboxylate (mp 96-98 C). The product was recrystallized using a mixture of petroleum ether:ethyl acetate (9:1), and gave 94 g of pure methyl 6-n-Pentyl-2-hydroxy-4-oxo-cyclohex-2-ene-1-carboxylate (melting point of 98-100 C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[S:32]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1)(=[O:35])(=[O:34])[NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:44][CH2:43][CH2:42][C:39]4[CH:38]=[CH:37][C:36]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:41][CH:40]=4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(CCNC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(4-sulfamoylphenyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=629.94 (M+H+); retention time=0.75 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[H-].[Na+].[Cl:16][C:17]([CH2:19]Cl)=[CH2:18]>CN(C)C=O>[Cl:16][C:17](=[CH2:18])[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1
Reactant: C=C(Cl)CCl
Reactant: OC[C@H]1COc2ccc(O)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cl)COc1ccc2c(c1)OC(CO)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.36 g (7.47 mmole) of (2S)-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl)methanol in 50 mL of N,N-dimethylformamide was added 0.36 g (9.0 mmole) of 60% sodium hydride/mineral oil dispersion and the mixture stirred for 30 minutes at room temperature under nitrogen. Next 1.0 mL (11 mmole) of 2,3-dichloro-1-propene was added and the reaction heated at 60° C. under nitrogen for 40 hours. The solvent was removed in vacuum and replaced with 200 mL of methylene chloride. The solution was washed with 50 mL of 0.1 N aqueous HCl and with water, dried over sodium sulfate, filtered and concentrated in vacuum to ˜2 g of a very dark oil. The oil was column chromatographed on silica gel with 20% hexane/methylene chloride and the product fractions combined and concentrated in vacuum to give 1.1 g of the (S)-enantiomer of the title compound as a pale yellow oil. 1H-NMR (d6-DMSO): doublet 7.76 δ (1H); doublet 6.53 δ (1H); doublet of doublets 6.45 δ (1H); doublet 5.66 δ (1H); doublet 5.48 δ (1H); broad singlet 5.04 δ (1H); singlet 4.6 δ (2H); doublet of doublets 4.25 δ (1H); multiplet 4.12 δ (1H); doublet of doublets 3.92 δ (1H); multiplet 3.6 δ (2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C(O)C.[Pt]=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH:14]2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2cccnc2-c2cccc(F)c2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cccc(NC(=O)C2CCCNC2c2cccc(F)c2)c1
Reaction time: 8 h

Procedure:
A mixture of N-(3-tert-butylphenyl)-2-(3-fluorophenyl)nicotinamide (501.2 mg, 1.4 mmol), platinum oxide (51.9 mg, 0.21 mmol), and concentrated HCl (400 μL, 5.2 mmol) in 5 mL of ethanol was stirred vigorously under hydrogen balloon overnight. The mixture was filtered, and the solids washed with 25 mL of methanol three times. The combined solution was dried under reduced pressure. To the residue was added 30 mL of saturated sodium bicarbonate and 150 mL of EtOAc. The organic layer was separated, and dried over sodium sulfate. Evaporation of solvent gave the crude 2-(3-fluorophenyl)piperidine-3-carboxylic acid (3-tert-butylphenyl)amide as a brown solid, which was taken on directly to the next step. MS: (ES) m/z 355.7 (M+H+).
Reaction SMILES: N.[H][H].[CH2:4]([NH2:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:4]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCN
Agent: N
Product: CCCCCCCCCCCCNCCCCCCCCCCCC

Procedure:
The same procedure as in Example 13 was repeated except for using the catalyst (K) produced in Preparation Example 10 in place of the catalyst (G), flowing ammonia and hydrogen through the autoclave at rates of 13.1 g (0.77 mol)/h and 4.3 L (0.19 mol)/h, respectively, thereby conducting the reaction for 6 h. The resultant reaction product was analyzed in the same manner as in Example 7. As a result, it was confirmed that the conversion of the raw alcohol was 65.5%, the selectivity to lauryl amine was 85.5%, the amount of dilauryl amine produced is 7.3%, and the amount of the other by-products produced was 2.2%.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10](=[N:16]O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:28][C:27]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:30][CH:29]=3)=[N:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(N(C)C)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(N(C)C)cc1
Yield: 32.9 %

Procedure:
Ethyl 3-(4-dimethylaminophenyl)-2-hydroxyimino-3-oxopropionate (3.8 g) and 4-nitrobenzylamine (2.8 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-dimethylaminophenyl)-2-(4-nitrophenyl)-imidazole-4-carboxylate (1.8 g), melting point 240-242° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[N:50]=[C:49]2[N:51]([CH3:60])[C:52](=[O:59])[N:53]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:48]2=[CH:47][CH:46]=1>ClCCl>[CH3:56][C:55]([CH3:58])([CH3:57])[CH2:54][N:53]1[C:48]2[C:49](=[N:50][C:45]([CH2:44][CH2:43][CH2:42][CH2:41][NH:40][C:6]([C:3]3[CH:4]=[CH:5][O:1][N:2]=3)=[O:8])=[CH:46][CH:47]=2)[N:51]([CH3:60])[C:52]1=[O:59]
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCCN)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCCNC(=O)c3ccon3)nc21
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-isoxazolecarboxylic acid (0.02 g, 0.18 mmol), and triethylamine (0.1 mL, 0.72 mmol) in dichloromethane (2 mL) was added HATU (0.07 g, 0.18 mmol). The resulting mixture was stirred 20 minutes. To this mixture was added 38-2 (0.04 g, 0.14 mmol) and the resulting mixture was stirred room temperature overnight. The mixture was washed with water and concentrated. Flash column separation using a 10-70% ethyl acetate/hexane gradient gave 38-3. (0.045 g, 85%). HRMS (M+H)+: observed=386.2188, calculated=386.2187
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([Si](C)(C)C)[N:12]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C(=O)N([Cl:26])C(=O)C1>CC#N>[Cl:26][C:13]1[N:12]=[N:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[Si](C)(C)c1cn(-c2ccc([N+](=O)[O-])cc2)nn1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2cc(Cl)nn2)cc1
Temperature: 80 °C

Procedure:
To a mixture of 1-(4-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (0.5 g, 1.9 mmol) and silica gel (2.9 g) in anhydrous CH3CN (10 mL) was added NCS (1.1 g, 6.7 mmol). The mixture was heated to 80° C. for 24 h. The reaction was cooled, filtered and concentrated in vacuo. The resulting crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give 4-chloro-1-(4-nitrophenyl)-1H-1,2,3-triazole. 1H NMR (CDCl3, 400 MHz) δ 8.39 (dd, 2H), 8.02 (s, 1H), 7.89 (dd, 2H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O>CN(C)C=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14]([I:17])[N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2nn3ccnc3s2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2nn3c(I)cnc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
2-(4-Fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazole (0.6 g, 2.55 mmol) was dissolved in N,N-dimethylformamide (10 mL) and N-iodosuccinimide (0.63 g, 2.81 mmol) was added in one portion. The reaction mixture was stirred at room temperature overnight in the absence of light. The yellow suspension was filtered and rinsed with diethylether (2×2 mL) to give 2-(4-fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole as a white solid (0.65 g, 71%). The filtrate was evaporated and the residue was triturated with diethylether (6 mL) and filtered. This solid was purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0:10 to 1:9) to give 2-(4-fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole as a white solid (0.15 g, 16% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:27]1[C:31]([CH:32]=O)=[CH:30][N:29]=[CH:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([CH2:32][C:31]3[NH:27][CH:28]=[N:29][CH:30]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=Cc1cnc[nH]1
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2cnc[nH]2)C2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (134 mg, 0.34 mmol) was dissolved in absolute CH2Cl2 (10 ml), and 1H-imidazole-5-carbaldehyde (65 mg, 0.67 mmol), NaBH(OAc)3 (143 mg, 0.67 mmol) and glacial acetic acid (41 mg, 0.67 mmol) were added. The mixture was stirred at room temperature for 2.5 hours. The mixture was then filtered and the organic phase was extracted by shaking three times with HCl (1 N). The aqueous phase was brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by preparative HPLC (as described under Example 14 in MeOH/H2O/Et2NH 80:20:0.1). MeOH was evaporated off from the product fraction, the aqueous phase was extracted by shaking three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated. A colorless solid was isolated.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20](=[O:29])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)[N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:5])C.[OH-].[K+].Cl>C1COCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:20]([CH2:19][N:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[N:8]2)=[O:29])=[N:23][CH:24]=1
Reactant: CCOC(=O)c1cc(OCCOCCOC)nn1CC(=O)Nc1ccc(Cl)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOCCOc1cc(C(=O)O)n(CC(=O)Nc2ccc(Cl)cn2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1.2 g 2-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-[2-(2-methoxy-ethoxy)-ethoxy]-2H-pyrazole-3-carboxylic acid ethyl ester in 5 ml THF 10 ml of a aqueous KOH solution (10%) were added and the reaction mixture was stirred for 4 h at RT. Then the mixture was acidified with half concentrated hydrochloric acid to pH 3 and the precipitate collected by filtration and washed with 10 ml of water The product was obtained as a white solid which was dried under reduced pressure. Yield: 310 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].CC1C=CC(S([CH2:19][N+:20]#[C-:21])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH:21]=[N:20][CH:19]=1
Reactant: O=Cc1ccccn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(-c2cnco2)nc1
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of picolinaldehyde (2.3 g, 42.6 mmol), TosMIC (4.4 g, 45.2 mmol) and K2CO3 (3.4 g, 48.8 mmol) in methanol (70 mL) was reflux for 2 h. The reaction was cooled to room temperature, then the mixture was concentrated and purified by silica gel column chromatography to give the desired product (3.05 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)(=[O:22])=[O:21]
Reactant: N#Cc1ccc(CO)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C#N)c(F)c1
Reaction time: 1.5 h

Procedure:
2-Fluoro-4-hydroxymethylbenzonitrile (1.3 g, 8.6 mmol; see step (ii) above) was dissolved in 50 mL of CH2Cl2 and cooled on an ice bath. Triethylamine (0.87 g, 8.6 mmol) and methanesulfonyl chloride (0.99 g, 8.7 mmol) were added. After stirring for 1.5 h the reaction mixture was washed with 1M HCl. The organic phase was dried (Na2SO4) and evaporated. The product could be used without purification. Yield of a colourless oil: 1.8 g (92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH:27]([F:29])[F:28])[CH:23]=[CH:22][C:21]=1B(O)O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([O:26][CH:27]([F:28])[F:29])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: OB(O)c1ccc(OC(F)F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1c(-c2ccc(OC(F)F)cc2Cl)ccnc1OCc1ccccc1
Yield: 70 %

Procedure:
To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (5.0 g, 18.9 mmol) in DME/H2O, was added 2-chloro-4-difluoromethoxy-phenylboronic acid (Wilde, et al. WO 99/01454, which is incorporated by reference herein in its entirety) (4.20 g, 18.9 mmol), Ba(OH)2 8H2O (5.96 g, 18.9 mmol), and Pd(PPh3)2Cl2 (0.769 g, 1.10 mmol) were treated as in Part A of Example 113 to give 5.40 g (70%) of 2-benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridine as a viscous oil. The crude intermediate was used in the following step.