Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][OH:27])[O:23][C:22]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1.O[C:30]1[CH:34]=[CH:33][O:32][N:31]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[C:17]([O:16][C:14]([NH:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N:21]3[CH2:25][C@H:24]([CH2:26][O:27][C:30]4[CH:34]=[CH:33][O:32][N:31]=4)[O:23][C:22]3=[O:28])=[CH:3][C:2]=2[F:1])[CH2:9]1)=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Reactant: Oc1ccon1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reaction time: 18 h
Yield: 66.7 %

Procedure:
3-(3-Fluoro-4-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (5 g, 12.7 mmol), 3-hydroxyisoxazole (2.15 g, 25.3 mmol), and 1,1′-(azodicarbonyl)dipiperidine (6.39 g, 25.3 mmol) were suspended by stirring in dry tetrahydrofuran (100 ml) under nitrogen and cooled to 5° in an ice-bath. Tributylphosphine (5.12 g, 25.3 mmol) was added dropwise over 20 minutes, and the solution stirred 18 hours, allowing the temperature to rise to ambient. Reduced azo compound was filtered off, and the solution evaporated to dryness and the residue triturated with ether. The residue was purified by chromatography on a 90 g Biotage silica column, eluting with a gradient from 50 to 75% EtOAc in isohexane. Relevant fractions were combined and evaporated to give the product (3.92 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccnc(Cl)c1

Procedure:
2-Chloroisonicotinic acid (707 mg, 4.49 mmol) was suspended in thionyl chloride (10 mL), followed by stirring under heating and reflux for 7 hours. The reaction mixture was concentrated under reduced pressure to afford 2-chloroisonicotinoyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[C:6]([NH:8][C:9](=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.N>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CC1
Yield: 90.5 %

Procedure:
A mixture of N-{5-bromo-2-[(cyclopropylmethyl)amino]phenyl}-3,3-dimethylbutanamide (Step C, 761 mg, 2.24 mmol) and p-toluenesulfonic acid monohydrate (426 mg, 2.24 mmol) in toluene (40 mL) was stirred under reflux for 23 h with Dean-Stark apparatus. Water (10 mL) and aqueous ammonia (5 mL) were added and the mixture was extracted with ethyl acetate (20 mL×2). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1 as eluent) to give the title compound (651 mg, 90%) as a brown oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([S:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:13]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:12]=2[CH:33]=1.[C:34](Br)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[C:34]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([S:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[N:13]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:12]=2[CH:33]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)=CCn1c(SCCCNC(=O)OC(C)(C)C)nc2ccc(N)cc21
Reactant: O=C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(SCCCNC(=O)OC(C)(C)C)nc2ccc(NC(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
24 mg (0.07 mmol) of cesium carbonate were added to a solution of 58 mg of tert-butyl {3-[6-amino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-ylsulfanyl]propyl}carbamate (obtained analogously to examples 1a-c) in 5 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 17 μl (0.15 mmol) of benzoyl bromide were added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and partitioned between water and dichloromethane. The organic phase was dried, concentrated under reduced pressure and purified by means of preparative HPLC (acetonitrile/water+0.5% trifluoroacetic acid, gradient: 20/80 to 100/0). 33 mg (44%) of the desired product were obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(O)(C)C.O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrCCCc1ccccc1
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC(=O)N1CCC(OCCCc2ccccc2)CC1
Reaction time: 4 h
Yield: 27.4 %

Procedure:
1-Acetylpiperidin-4-ol (Preparation 193, 8 g, 60 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to a stirred suspension of sodium hydride (50% wt dispersion in oil, 3.68 g, 80 mmol) in N,N-dimethylformamide (50 ml) at room temperature under nitrogen. After stirring the reaction mixture for 4 hours, 1-bromo-3-phenylpropane (12.94 g, 65 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to the solution at 0° C. and the reaction mixture was stirred for a further 4 h. The solution was diluted with isopropyl alcohol (20 ml) and water (100 ml) and then evaporated to give a semi solid. Water (100 ml) was added and the solution was extracted with petroleum ether (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give an orange oil (4.3 g, 27%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[N+](=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N-]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH3:22][N:12]1[C:13](=[O:21])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@H:11]1[CH2:10][CH2:9][C@@H:8]1[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C@@H:2]2[O:1][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of 17β-hydroxy4-methyl-5α-4-azaandrostan-3-one (2.37 g, 7.75 mmole) in methylene chloride (50 ml) was added ethyl diazoacetate (5.5 g, 48 mmole) and rhodium diacetate dimer (50 mg) intermittently in small portions during 60 hours resulting in ca. 35% conversion to product. The mixture was passed through a flash silica gel column eluted with 1.5% MeOH in CH2Cl2 to give the semi-purified product which was repurified via another flash silica gel column eluted with 60-95% EtOAc in hexane to give the title product, (Rf 0.3/EtOAc) mp. 39°-41° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[CH2:19][CH:18]([CH2:20][OH:21])[CH2:17][C:16]1=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CS(C)=O>[CH2:8]([N:15]1[C:16](=[O:22])[CH2:17][CH:18]([CH:20]=[O:21])[CH2:19]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CC(CO)CN1Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
Triethylamine and a pyridine-sulfur trioxide complex were added to a DMSO solution of 1-benzyl-4-(hydroxymethyl)pyrrolidin-2-one and stirred at room temperature for 2Hours. Thereafter, its work-up and purification were carried out in the standard method to obtain 1-benzyl-5-oxopyrrolidine-3-carboaldehyde. EI: 203.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH2:14]([N:16]([CH2:17][CH3:18])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11])[CH3:15]
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: CCNCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(CC)c1ccc(C#N)cc1C(F)(F)F
Temperature: 135 °C
Reaction time: 16 h

Procedure:
A mixture of 4-bromo-3-(trifluoromethyl)-benzonitrile (Yonezawa et al., Synthetic Communications (1996), 26, 1575-1578; 6.0 g, 24 mmol), diethylamine (8.3 mL, 80 mmol) and 25 mL N,N-dimethylacetamide is stirred in a tightly closed vessel for 16 hours at 135° C. After cooling, the reaction mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined organic extracts are dried (Na2SO4) and the solvent is evaporated off under reduced pressure. The crude product is purified by column chromatography on silica gel, eluent hexane/ethyl acetate to give the title compound as an orange oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[CH2:50]([O:52][C:53]([CH:55]1[CH2:60][CH2:59][N:58]([C:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=2)[CH2:57][CH2:56]1)=[O:54])[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]([CH:55]1[CH2:56][CH2:57][N:58]([C:61]2[CH:66]=[CH:65][C:64]([NH:67][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:63][CH:62]=2)[CH2:59][CH2:60]1)=[O:54])[CH3:51]
Reactant: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (926 mg, 3.6 mmol), triethylamine (910 mg, 1.25 mL, 9.0 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 2.51 g, 5.4 mmol) and 1-(4-amino-phenyl)-piperidine-4-carboxylic acid ethyl ester (3.6 mmol, prepared above) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was diluted with. EtOAc, and washed twice with water. The organic phase was then dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (gradient elution with 10-50% ethyl acetate in hexanes) to provide 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid ethyl ester. HRMS calcd for C25H24F3N3O4 (M+H) 488.1792, obsd 488.1792.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2C[CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: c1nc(-c2cnn(C(CC3CC3)C3CCCC3)c2)c2cc[nH]c2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1SC.[NH2:22][OH:23]>C(O)(C)C>[OH:23][NH:22][C:7]1[N:6]([CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=2[O:2][CH3:1])[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: NO
Reactant: COc1ccccc1CN1Cc2ccccc2N=C1SC
Solvent: CC(C)O
Product: COc1ccccc1CN1Cc2ccccc2N=C1NO

Procedure:
0.6 g (2.01 mmol) 3-(2-methoxybenzyl)-2-(methylthio)-3,4-dihydroquinazoline and 265 mg hydroxylamine in 10 mL isopropanol were heated at reflux for approx. 36 hours. For workup, the mixture was evaporated, the resulting residue was recrystallized in a mixture of diethyl ether/methyl tert-butyl ether 1:1 and then lyophilized by MPLC (silica gel: Bischoff Prontoprep 60-2540-C18E, 32 μm; mobile phase: CH3CN/H2O+0.1% acetic acid). 300 mg white solids.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[OH:11][C:12]([CH3:27])([CH3:26])[CH2:13][CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:14][CH2:13][C:12]([CH3:27])([OH:11])[CH3:26])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1OCCC(C)(C)O
Temperature: 80 °C
Yield: 70 %

Procedure:
4-Bromo-2,6-dimethylphenol (2.00 g, 9.95 mmol), toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester (Intermediate 10, 2.83 g, 10.9 mmol) and potassium carbonate (1.01 g, 10.9 mmol) are combined in N,N-dimethylformamide (50 mL) and heated at 80° C. for 24 hours. The mixture is cooled, poured into water and extracted with diethyl ether. The organic phase is dried and the solvent removed. The residue is purified by flash chromatography (0-50% ethyl acetate in cyclohexane) to give the title compound (Yield 2.00 g). GC (METHOD 1): tR=11.26 min; Mass spectrum (EI+): m/z=286/288 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:19](Cl)=[O:20])([CH3:15])([CH3:14])[CH3:13]>COCCOC>[C:26]([C:23]1[CH:22]=[C:18]([CH:17]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:24]=1[OH:25])[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.6 %

Procedure:
A suspension of 9.2g (0.061 mole) of p-aminophenylacetic acid in 150 ml of 1,2-dimethoxyethane was added to a suspension of 8.0g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then filtered. The filtrate was thereafter diluted with water and chilled. The resulting precipitate was collected and recrystallized from a mixture of ethanol and water to give 1.32g of yellow crystalline 4-(3,5-di-t-butyl-4-hydroxybenzamido)phenylacetic acid, m.p. 253°-254° C. Analysis: Calculated for C23H29NO4 : %C, 72.0; %H, 7.6; %N, 3.6; Found: %C, 72.0; %H, 7.7; %N, 3.4.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](C(F)(F)F)[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.OC(COC1C=CC(OC)=CC=1)[CH2:33][NH:34]C(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:33]#[N:34])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C(F)(F)F)c2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C#N)cc2)cc1

Procedure:
N-(2-hydroxy-3-(3-N,N-dimethylphenoxy)propyl)-1,1-dimethyl-2-(-4-methoxyphenyl)ethylamine, GC/MS 251 (100), 176 (9), 163 (5), 138 (11), 137 (6), (8), 125 (10), 121 (23), 114 (46), 108 (6), 77 (6), 76 (7), (10), 70 (14), 42 (8).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[Cl-].[CH3:22][Zn+].O>O1CCCC1.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>[CH3:22][C:2]1[N:7]=[C:6]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: C[Zn+]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(Cl)nc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(C)nc32)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
The synthesis was performed with reference to the known literature (US 2006/0148801). A solution of 6-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.38 g, 1.2 mmol) in tetrahydrofuran (20 mL) was added with tetrakis(triphenylphosphine)palladium(0) (0.069 g, 0.060 mmol) under an argon atmosphere. Then, the mixture was added dropwise with a 2 M solution of methyl zinc chloride in THF (3.6 mL, 7.2 mmol), and then the mixture was stirred at 60° C. for 48 hours. The reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (90:10→50:50)) to obtain 6-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.28 g, 81%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC2CCCCC=2C=1C(OCC)=O.[Cl:40]C1C=CC=CC=1S(Cl)(=O)=O>>[Cl:40][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[S:7]([NH:10][C:11]1[S:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[C:12]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8]
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: CCOC(=O)c1c(N)sc2c1CCCC2
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2Cl)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and 2-chlorobenzene-sulphonyl chloride
Reaction SMILES: [Na+].[I-:2].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O)CCCC>[Cu]I>[I:2][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Brc1ccccc1C1CCCCC1
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCCO
Product: Ic1ccccc1C1CCCCC1
Temperature: 130 °C
Reaction time: 40 h
Yield: 98.9 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), NaI (300 mg, 2.00 mmol), evacuated and backfilled with argon. Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %), l-bromo-2-cyclohexylbenzene (97% pure; Lancaster; 186 μL, 1.00 mmol), n-pentanol (1 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 40 h. The resulting suspension was allowed to reach room temperature and filtered through silica gel (1×0.5 cm) eluting with hexane (50 mL). The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (hexane) to provide the known 1-iodo-2-cyclohexylbenzene (283 mg, 99% yield; ca. 97% pure) as a colorless liquid. See McGuine, T. H.; Dull, M. F. J. Am. Chem. Soc. 1947, 69, 1469. 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, J=7.5, 1.2 Hz, 1H), 7.32 (td, J=7.5, 1.2 Hz, 1H), 7.23 (dd, J=7.5, 1.7 Hz, 1H), 6.90 (td, J=7.5, 1.7Hz, 1H), 2.81 (tt, J=11.7, 3.0Hz, 1H), 1.97-1.74 (m, 5H), 1.55-1.23 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 149.3, 139.5, 128.4, 127.6, 126.6, 101.5, 48.5, 33.4, 26.8, 26.1.
Reaction SMILES: O[CH:2]1[CH2:7][NH:6][C:5](=[O:8])[N:4]2[C:9]3[N:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12.C(Cl)Cl>>[N:15]1[C:9]2[N:4]3[C:5](=[O:8])[NH:6][CH:7]=[CH:2][C:3]3=[CH:11][C:10]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1NCC(O)c2cc3cccnc3n21
Solvent: ClCCl
Product: O=c1[nH]ccc2cc3cccnc3n12
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a cooled (0° C.) solution of 6,7,8,9-Tetrahydro-6-hydroxypyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidin-9-one (1 g, 4.2 mmol) and TEA (1.74 ml, 13 mmol) in CH2Cl2 (200 ml) MsCl (320 μl, 4.2 mmol) was dropwise added. The reaction mixture was stirred for 30 min. at the same temperature and the organic solution was washed with saturated aq. NH4Cl and with water. The organic solution was dried and evaporated to obtain 11a (730 mg, 95%), as a white solid without further purification
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:13][C:3]1[CH:4]=[C:5]([N:8]2[N:12]=[CH:11][CH:10]=[N:9]2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-n2nccn2)cc1CO
Solvent: ClCCl
Product: Cc1ccc(-n2nccn2)cc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a stirred solution of (2-methyl-5-(2H-1,2,3-triazol-2-yl)phenyl)methanol (100 mg, 0.53 mmol) in dichloromethane (5 mL), thionyl chloride (155 mg, 1.3 mmol) was added dropwise at 0° C. and stirred for 1 h. Then the mixture was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated under reduced pressure at rt and dried under high vacuum to yield the title compound (90 mg, 83%). The compound was directly used for the next step without further purification. [TLC Rf=0.66 (ethyl acetate/hexane 30:70)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[O:5][CH:6]([CH3:10])[C:7](O)=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([Cl:14])[CH:13]=1)[O:5][CH:6]([C:7]1[S:18][C:17]([NH2:19])=[N:16][N:15]=1)[CH3:10]
Reactant: NNC(N)=S
Reactant: CC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(Oc1cc(Cl)cc(Cl)c1)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser, was charged with 9.4 grams (0.040 mole) of 2-(3,5-dichlorophenoxy)propanoic acid, (3.6 grams, 0.040 mole) of thiosemicarbazide and 30 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (6.7 grams, 0.044 mole) was slowly added (for 22 minutes) while maintaining the temperature within 85°-90° C. The resulting mixture was refluxed for 60 minutes. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), fifty (50) milliliters of water was added and 50 percent solution of NaOH was also added until the pH of the solution was 10; an oil formed. The oil was extracted with diethylether, dried over MgSO4, filtered, and topped in a roto-vac at 70° C. to yield 7.9 grams of a pale yellow oil of 5-[1-(3,5-dichlorophenoxy)ethyl]-2-amino-1,3,4-thiadiazol.