Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)([OH:15])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCOC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Yield: 100 %

Procedure:
A solution of (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1-hydroxy-2-(2-methoxyethoxy)-ethyl)piperidine-1-carboxylate (30 mg, 0.073 mmol) in 20% TFA/CH2Cl2 (5 mL) was stirred at 0° C. for 30 min. Evaporation of the solvent afforded (1S)-1-(3-chlorophenyl)-2-(2-methoxy-ethoxy)-1-((3R)-piperidin-3-yl)ethanol (30 mg, 0.073 mmol 100%). MS (E/Z): 314 (M+H+).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][N:35]=1)[C:28]#[N:29].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([C:28]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:29]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:42])[F:43])=[CH:36][N:35]=1
Reactant: N#Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (0.90 g), 3-chloro-4-(3-chloro-5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.80 g), anhydrous iron (III) chloride (0.40 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:33])[CH2:18][CH2:19][C:20]2[CH:21]=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:33])[CH2:18][CH2:19][C:20]2[CH:21]=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:32])=[O:42])=[CH:27][CH:26]=2)=[CH:14][CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(SC)cc2)cc1)OCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(S(C)=O)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 16 %

Procedure:
A mixture of N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionamide (98 mg), m-chloroperbenzoic acid (60 mg) and tetrahydrofuran (5 ml) was stirred at room temperature for 4 hr. 10% aqueous sodium sulfite solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous potassium carbonate solution, and then with saturated brine, dried (MgSO4) and concentrated. The residue was purified by preparative HPLC to give N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-methylsulfinylphenyl)-4-isoxazolyl]propionamide.
Reaction SMILES: [Na:1].C(O)C.[NH2:5][C:6]1[S:10][N:9]=[N:8][C:7]=1[C:11]([O:13]CC)=[O:12]>O>[Na:1].[Na:1].[Na:1].[C:11]([C:7]1[N:8]=[N:9][NH:5][C:6]=1[SH:10])([OH:13])=[O:12]
Reactant: CCOC(=O)c1nnsc1N
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nn[nH]c1S
Reaction time: 1 h

Procedure:
To a solution of 4.6 g. (0.20 mol.) of sodium and 250 ml. of absolute ethanol was added under a nitrogen atmosphere 8.65 g. (0.05 mol.) of 5-amino-4-carbethoxy-1,2,3-thiadiazole. The reaction mixture was stirred one hour, 5 ml. of water was added and the mixture was refluxed for 12 hours. After cooling, the mixture was filtered and the solid product was washed with ethanol and ether and dried to give 4-carboxy-1,2,3-triazole-5-thiol trisodium salt.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)(=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl[Sn](Cl)(Cl)Cl.Cl>C1C=CC=CC=1>[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: c1ccsc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)c1cccs1
Yield: 75.6 %

Procedure:
In a 5 liter-five-necked flask, 112.5 g (1.34 mol) of thiophene, 300 g (1.37 mol) of n-dodecanoyl chloride and 2.25 liter of dry benzene were placed and cooled below 0° C. To the mixture under stirring, 148.5 g (5.70×10-1 mol) of SnCl4 was added dropwise in 1 hour below 0° C. The mixture was stirred for 30 min. below 0° C., followed by stirring for 4 hours while being gradually restored to room temperature. After the reaction, 2 liter of 10% HCl was added to the reaction mixture, followed by stirring for 10 min. The separated organic layer was successively washed three times with 500 ml each of 10% HCl, water, 5% Na2CO3 and water, followed by drying with CaCl2 and distilling-off of the solvent to obtain 315 g of a crude product. The crude product was subjected to reduced-pressure distillation under an atmosphere of nitrogen to obtain 270 g of a pure product (yield: 75.7%). b.p.: 146° C./0.65 mmHg
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:37]([NH2:40])([CH3:39])[CH3:38]>O1CCCC1>[CH:37]([NH:40][C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[N:16][CH:15]=[CH:14][CH:13]=2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:9]=1)=[O:20])([CH3:39])[CH3:38]
Reactant: CC(C)N
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 3 (1 eq) and triethylamine (3 eq) in tetrahydrofuran (0.08M) at 0° C. was added isobutyl chloroformate (1.8 eq). After stirring at 0° C. for 2 hours, isopropylamine (5 eq) was added and the mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid which was stirred in ether at room temperature for 3 hours and filtered to afford the N-Isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:31][CH2:32][CH3:33]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:31][CH2:32][CH3:33]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: CCCBr
Product: CCCOc1ccc(-c2nc(CNC(=O)c3ccccc3OCC)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 373 and 1-bromopropane, white powdery N-[2-(3-difluoromethoxy-4-propoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 98.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:25]4[C:26](=[O:35])[O:27][C@@H:28]([CH2:29]OS(C)(=O)=O)[C@@H:24]4[CH2:23][O:22][C:21]=3[CH:36]=2)[C:13](=[O:37])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:25]4[C:26](=[O:35])[O:27][C@@H:28]([CH2:29][N:43]5[C:39](=[O:49])[C:40]6[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=6)[C:42]5=[O:44])[C@@H:24]4[CH2:23][O:22][C:21]=3[CH:36]=2)[C:13](=[O:37])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OC[C@@H]1OC(=O)N2c3ccc(N4CCN(C(=O)OCc5ccccc5)CC4=O)cc3OC[C@@H]12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C(OCc1ccccc1)N1CCN(c2ccc3c(c2)OC[C@H]2[C@H](CN4C(=O)c5ccccc5C4=O)OC(=O)N32)C(=O)C1
Yield: 79 %

Procedure:
Using compound 4-((3R,3 aS)-3-((methylsulfonyloxy)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)-3-oxopiperazin-1-carboxylic acid benzyl ester (0.916 g, 1.725 mmol), and phthalimide potassium (0.479 g, 2.558 mmol) as starting materials, preparation following the method as described in Example 1 (d) afforded white solid 0.794 g, yield: 79.1%.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C@@H:23]2[CH2:25][C@H:24]2[C:26]([NH:28][CH3:29])=[O:27])[CH2:6]1)(=O)C.O(P(O[C:47]1[C@H:48]([CH3:71])[C@H:49]2[C@@H:66]([C@H:67]([OH:69])[CH3:68])[C:65](=[O:70])[N:50]2[C:51]=1[C:52]([O:54][CH2:55]C1C=CC([N+]([O-])=O)=CC=1)=[O:53])(OC1C=CC=CC=1)=O)C1C=CC=CC=1>>[OH:69][C@@H:67]([C@H:66]1[C:65](=[O:70])[N:50]2[C:51]([C:52]([O:54][CH2:55][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:53])=[C:47]([S:4][C@@H:5]3[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)=[O:11])[C@H:7]([C@@H:23]4[CH2:25][C@H:24]4[C:26]([NH:28][CH3:29])=[O:27])[CH2:6]3)[C@H:48]([CH3:71])[C@H:49]12)[CH3:68]
Reactant: CNC(=O)[C@@H]1C[C@H]1[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: CNC(=O)[C@@H]1C[C@H]1[C@@H]1C[C@H](SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 223.7 %

Procedure:
The same procedure as in EXAMPLE 1a and 1b was carried out by using trans-2-[(2S,4S)-4-acetylthio-N-(4-nitrobenzyloxycarbonyl) pyrrolidin-2-yl]-N-methylcyclopropanecarboxamide (180 mg, 0.42 mmol)and 4-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate(203 mg, 0.34 mmol) to give 4-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[trans-2-(N-methylaminocarbonyl) cyclopropyl]-N-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (340 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A solution of tert-butyl 4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperidine-1-carboxylate (0.0542 g, 0.144 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0211 g, 0.144 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(2-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0524 g, 72%).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>>[F:23][C:20]([F:21])([F:22])[C:16]1[CH:15]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc(C2=CCN(Cc3ccccc3)CC2)c1
Agent: Cl
Product: FC(F)(F)c1cccc(C2CCNCC2)c1
Yield: 96.1 %

Procedure:
Beginning with 1-Benzyl-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydro-pyridine (1.44 g), 1 g of the title compound as HCl salt was recovered by the procedure described in preparation 9. m.p. 202° C. (HCl); MS m/z (rel. intensity, 70 eV) 229 (M+, 44), 228 (33), 83 (12), 57 (54), 56 (bp).
Reaction SMILES: [CH3:1][C:2]([NH:23][CH:24]=O)([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Cl>C(O)C>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([F:19])([F:18])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([NH:23][CH3:24])([CH3:22])[CH3:1])=[CH:4][CH:5]=2)([F:20])[F:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(F)(F)C(F)(F)c2ccc(C(C)(C)NC=O)cc2)cc1
Agent: Cl
Solvent: CCO
Product: CNC(C)(C)c1ccc(C(F)(F)C(F)(F)c2ccc(C)cc2)cc1

Procedure:
By following essentially the same procedures described in Example 6, N-[α,α-dimethyl-4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide is reduced to 4-(p-methyl-α,α,β,β-tetrafluorophenethyl)-α,αN-trimethylbenzylamine. The crude oily base is converted to the hydrochloride salt by treating a solution in ethanol with a slight excess of 8N hydrogen chloride in ethanol. Dilution with absolute ether precipitates the white crystalline hydrochloride, m.p. 189°-190° C. The melting point is unchanged by recrystallization from isopropyl alcohol-ether.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[N:4]([CH3:13])[N:3]=1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[Si:19]([O:12][CH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH3:13])[N:3]=[C:2]2[I:1])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1nc(I)c2cc(CO)ccc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cn1nc(I)c2cc(CO[Si](C)(C)C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of (3-iodo-1-methyl-1H-indazol-5-yl)-methanol (810 mg, 2.81 mmol) in DMF (9 mL) was added imidazole (479 mg, 7.03 mmol) followed by tert-butyldimethylsilyl chloride (466 mg, 3.09 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 10% EtOAc/hexanes to afford 732 mg (65%) of 5-(tert-butyldimethylsilanyloxymethyl)-3-iodo-1-methyl-1H-indazole as a pale yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.26-7.34 (m, 2H), 7.17-7.23 (m, 1H), 4.73 (s, 2H), 3.97 (s, 3H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.CO>O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]2[NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccc(OCCCCCl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Product: ClCCCCOc1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 65.1 %

Procedure:
A mixture of copper (II) acetate monohydrate (7.76 g), 1,2-diaminobenzene (2.10 g), 4-(4-chlorobutoxy]benzaldehyde (Step A) (5.0 g) is slowly heated to reflux in water (10 mL) and methanol (100 mL) and stirred at reflux for 1 hour. The mixture is cooled and a brown precipitate filtered off. The precipitate is suspended in methanol (100 mL) and hydrogen sulfide bubbled through for 30 minutes followed by nitrogen. The mixture is heated to reflux, cooled and filtered. All the filtrates are combined and 0.880 ammonium hydroxide added until just basic. The filtrates are diluted with an equal volume of water and the resulting pale-grey precipitate collected. The precipitate is recrystallized from methanol/water to give 3.8 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][C:5]2[N:4]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:23][N:24]=2)[N:3]=1
Reactant: Clc1cc(-c2ccncc2)c(Cl)nn1
Reactant: NNC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Clc1nn2c(-c3ccccc3)nnc2cc1-c1ccncc1
Yield: 41.7 %

Procedure:
A mixture of 3,6-dichloro-4-(pyridin-4-yl)pyridazine (390 mg, 1.7 mmol), benzoyl hydrazine (260 mg, 1.9 mmol), triethylamine (270 ml, 1.9 mmol) and p-toluenesulphonic acid (32 mg, 0.2 mmol) in xylene (mixture of isomers) (5 ml) was stirred and heated at reflux under nitrogen for 20 hours. The mixture was partitioned between dichloromethane and saturated aqueous potassium carbonate. The aqueous was further extracted with dichloromethane (×3). The combined extracts were dried (sodium sulphate), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 3% methanol/dichloromethane to afford the title compound (218 mg, 42%) as a pale yellow solid. 1H NMR (360 MHz, d6-DMSO) δ 7.60-7.69 (5H, m), 8.36-8.38 (2H, m), 8.72 (1H, s), 8.78-8.80 (2H, m). MS (ES+) m/e 308 [MH]+, 310 [MH]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: Nc1ccc(OCCCBr)cc1[N+](=O)[O-]
Solvent: O
Product: CN1CCN(CCCOc2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A 100 mL flask was charged with 4-(3-bromopropoxy)-2-nitroaniline (2.2 g, 8.02 mmol) and 4-methylpiperazine (10 mL) and stirred at 100° C. The reaction was monitored by LCMS and complete in 30 minutes. The reaction mixture was treated with water (100 mL) and sonicated in an ultrasonic bath. The resulting solid were filtered off and dried under reduced pressure to give 1.5 g of 4-(3-(4-methylpiperazin-1-yl)propoxy)-2-nitroaniline (60% yield). MS (EI): 295 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:18]=[CH2:19]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[CH2:10][C:11](=[O:12])[CH2:19][CH2:18]2)[CH3:2]
Reactant: C=C
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc2c(c1)CCC(=O)C2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
39.1 g (0.20 mol) of 4-ethoxyphenylacetyl chloride in 200 ml of dichloromethane were added dropwise in the course of 1 hour at −78° C. to 53.4 g (0.4 mol) of aluminum chloride in 800 ml of dichloromethane. A vigorous stream of ethylene was subsequently passed in in the course of 15 minutes, and the mixture was allowed to come to room temperature and stirred for a further 3 hours. The dark red solution was cooled to 0° C. and carefully treated with 300 ml of ice-water. After phase separation, the organic phase was washed with 2N HCl (3×) and saturated sodium hydrogen carbonate solution, dried and evaporated on a rotary evaporator. After purification by column chromatography with petroleum ether/ethyl acetate (9:1, 8:2), 20.9 g (56% of theory) of a yellow syrup were obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1)=O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:58]=[N+:59]=[N-:60])(C)C>C1COCC1.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[N:60]=[N:59][N:58]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-{[4-cyano-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 21, 65 g) in THF (300 mL) was added triphenylphosphine (161 g, 0.615 mol) and diisopropylazodicarboxylate (124 g, 0.615 mol) at 0° C. The reaction mixture was stirred for 30 minutes. Trimethylsilylazide (71.1 g, 0.615 mol) was added dropwise at room temperature and then heated to reflux for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with ice-water. The organic layer was separated and washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using an eluent of 20% ethyl acetate in petroleum ether to yield 1-[4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:4][CH:3]=1
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Cl)cc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[S:7][N:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9])=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[S:7][N:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1nnsc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1nnsc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
Methyl 5-formyl-1,2,3-thiadiazole-4-carboxylate (460.0 mg, 0.0026 mol) was dissolved in ethanol (40 mL) and sodium tetrahydroborate (50 mg, 0.0013 mol) was added at 0° C. The orange solution was allowed to warm to room temp and was stirred for 30 minutes. The reaction was quenched with acetic acid and then purified by preparative LCMS to give the desired product (340 mg, 73%). MF═C5H6N2O3S; LCMS calculated for C5H7N2O3S(M+H)+: m/z=175.1.