Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[C:36](Cl)(=[O:40])[O:37][CH2:38][CH3:39].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(CNC(=O)C)COC1>ClCCl>[CH2:38]([O:37][C:36](=[O:40])[NH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=2[O:15][CH3:16])[CH2:4][O:5][CH2:6]1)[CH3:39]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Reactant: CCOC(=O)Cl
Agent: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)COC2)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added triethylamine (118 mg, 1.174 mmol) and ethyl carbonochloridate (84 mg, 0.783 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 192 to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]#[N:15])[N:6]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:34]=[N+:35]=[N-:36])(C)C.C(O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]2[NH:36][N:35]=[N:34][N:15]=2)[N:6]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1nc(Cc2ccccc2F)n2ccccc12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccccc1Cc1nc(-c2nnn[nH]2)c2ccccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 188 mg (0.75 mmol) of 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carbonitrile from example 18A, 18.6 mg (0.075 mmol) of dibutyltin oxide and 172 mg (1.50 mmol) of trimethylsilyl azide in 5 ml of toluene is heated under reflux for 20 h. Cooling is followed by addition of 5 ml of ethanol and stirring at RT for 15 h. The mixture is then concentrated, mixed with water and extracted with ethyl acetate. The organic phase is concentrated in vacuo, and the residue is purified by preparative HPLC. The product is taken up in ethyl acetate and clarified with activated carbon. The solid obtained after concentration is crystallized from dichloromethane. 40 mg (18% of theory) of the title compound are obtained as pale reddish crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.[C:24]([O:39][CH3:40])(=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O-])=[O:36]>CCOCC>[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:36])([O:39][CH3:40])=[O:38]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCC(=O)OC
Reaction time: 0.33 h
Yield: 83.1 %

Procedure:
To a stirred, ice-cold solution of 0.89 g (4.0 mM) amine (4) and dried triethylamine (1.2 mL) in dry ether (40 mL) is added dropwise over ca. 4 minutes a solution of acid chloride (7) (1.04 g, 4.6 mM) in 20 mL of dry ether. The resultant mixture is allowed to stir cold for 20 minutes, and then at room temperature overnight. After filtering off the triethylamine hydrochloride, the ether filtrate is concentrated in vacuo and the residue chromatographed on an 82 g silica gel column using 20% ethyl acetate/hexane as eluant to give 1.49 g (85%) of (8) as a waxy solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[CH:16]=[CH2:17]>C1COCC1>[CH2:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]1=[O:14])[CH:16]=[CH2:15]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: C=CCBr
Solvent: C1CCOC1
Product: C=CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Yield: 76 %

Procedure:
4-(tert-Butyloxycarbonyl)-piperazin-2-one (1.0 g, 5.0 mmol), EXAMPLE 40, is alkylated with allyl bromide (0.48 ml, 5.5 mmol) in THF (20 ml) using the procedure described in Example 92, Part A. The title compound (0.92 g, 3.8 mmol) is obtained as a colorless liquid after chromatographed (50% ethyl acetate/hexane). EI MS m/z 240 (M+); 1H NMR (CDCl3, 300 MHz) δ5.80-5.68 (m, 1H), 5.23-5.15 (m, 2H), 4.09 (s, 2H), 4.03 (d, 2H), 3.63 (t, 2H), 3,30 (t, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=CC)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:29]=[O+][O-].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[O:29])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC=Cc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Reaction time: 8 h

Procedure:
{(2R)-7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (10.5 g, 25.9 mmole) dissolved in 400 mL of methylene chloride was treated with excess ozone at −78° C. Diisopropylethylamine (11.5 mL, 66.0 mmole) was then added dropwise over 30 min and the mixture allowed to come to room temperature and stir overnight under a nitrogen atmosphere. The mixture was then diluted to 600 mL with methylene chloride, washed three times with 100 mL portions of 2N HCl (aq), twice with 200 mL portions of saturated aqueous sodium bicarbonate and with 200 mL of saturated brine. The solution was dried over magnesium sulfate, filtered and concentrated in vacuum to a crude brown oil, which was column chromatographed on silica gel with 10% hexane/methylene chloride to give 7.52 g of the (R)-enantiomer of the title compound as a yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ(2 H); doublet 7.62 δ(1 H); doublet 7.4 δ(2 H); doublet 7.0 δ(1 H); multiplet 4.4-4.6 δ(2 H); multiplet 4.2 δ(3 H); singlet 2.4 δ(3 H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[C:18](=[O:19])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](=O)[NH:15][C:14]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]1[C:18](=[O:19])[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([Cl:3])[NH:15][C:14]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NC(=O)N(Cc2ccccc2)C(=O)C1c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: O=c1[nH]c(Cl)c(-c2ccccc2)c(=O)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 64 ml of 50% ethanol, 300 ml (844 mmol) of phosphorus oxychloride was added drop by drop, with stirring under ice cooling conditions. To this solution, 120 g (380 mmol) of 3-benzyl-5-phenylpyrimidine-2,4,6(1H,3H)-trione was added little by little. This mixture was stirred at 50° C. for 30 minutes and then at 100° C. for 90 minutes. After cooling, the reaction mixture was poured into ice water and stirred for 1 hour. The resulting precipitate was collected by filtration, washed with water and n-hexane and dried to yield 112.89 g (94.7%, light white crystal) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19](OCC)=[O:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:2]=1[NH:1][C:19](=[O:20])[CH:18]2[S:17][CH3:16])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CSC
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A solution of 300 g. (1.52 mole) of 2-aminobenzophenone in 4 liters of methylene chloride was chilled to -40°C. and then treated with 204 g. (1.52 mole) of the ethyl α-(methylthio)acetate dissolved in 5 liters of methylene chloride. The reaction mixture was then cooled to -65°C. and treated dropwise with 500 ml. of a methylene chloride solution containing 164 g. (1.52 mole) of t-butylhypochlorite. After addition was complete, stirring was continued for 2 hr. at -70°C. The solution was then treated with 182 g. (1.8 mole) of triethylamine and allowed to come to room temperature overnight. The methylene chloride solution was washed twice with 3 liters of ice water followed by drying over sodium sulfate and concentrating the dried solution to a yellow oil under reduced pressure. The oil was taken into 1.5 liters of methanol treated with 1 liter of lN hydrochloric acid and refluxed for 2 hrs. After cooling in an ice bath 343 g. (79.9%) of crude product was recovered after filtering and drying. Two recrystallizations from toluene gave creamy white flakes; m.p. 130°C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:31][NH:32][CH3:33]>>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:27])([F:29])[F:28])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([N:32]([CH3:33])[CH3:31])=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Reactant: CNC
Agent: Cl
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)N(C)C)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (example 147c) and dimethylamine hydrochloride as starting materials and isolated (23 mg, 51%); MS (ESI, m/z): 442.5 (M+H+).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:19](O)=[O:20])[CH2:15][CH2:16][CH3:17].S(Cl)([Cl:30])=O>ClCCl.C(OCC)C>[CH2:14]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:19]([Cl:30])=[O:20])[CH2:15][CH2:16][CH3:17]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCC(CCCC)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCC(CCCC)C(=O)Cl
Temperature: 25 °C

Procedure:
500 μl (2.5 mmol) of dicyclohexylamine are added to 500 mg (2.5 mmol) of 2-butyloctanoic acid placed in 5 ml of dichloromethane, and the solution is stirred at room temperature for minutes. 200 μl (2.5 mmol) of thionyl chloride are then added and this mixture is stirred at room temperature for 2 hours. The reaction is diluted with ethyl ether. The precipitate is filtered off and rinsed with ethyl ether. Concentration of the filtrate gives the 2-butyloctanoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccc(F)cc2Sc2sc3ccccc3c21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Sc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:55]=2[F:61])=[CH:50][CH:49]=1)[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:60][C:58]1[CH:57]=[CH:56][C:55]([F:61])=[C:54]([C:51]2[CH:50]=[CH:49][C:48]([CH2:47][C@@H:38]([NH:37][C:10]([C:8]3[O:7][N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:9]=3)=[O:12])[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42])=[CH:53][CH:52]=2)[CH:59]=1
Reactant: CC(C)Cc1cc(C(=O)O)on1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Cc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.1 %

Procedure:
3-Isobutylisoxazole-5-carboxylic acid (9 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (0.3 mg). MS m/z [M+H]+ calc'd for C27H30ClFN2O5, 517.18. found 517.2.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:23]=2)[CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>Cl[Pd-2](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.O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:21]3[CH:20]=[C:19]4[C:24](=[CH:23][CH:22]=3)[NH:16][N:17]=[CH:18]4)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCNc1ccc2ncc(-c3ccc4[nH]ncc4c3)n2n1
Yield: 65.3 %

Procedure:
A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (140 mg, 0.50 mmol), (1H-indazole-5-boronic acid pinacol ester (150 mg, 0.60 mmol), dichloro-bis(triphenylphosphino) palladium (II) (20 mg, 0.025 mmol), potassium carbonate (110 mg, 0.75 mmol), acetonitrile (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 160° C. for 1000 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford butyl-[3-(1H-indazol-5-yl)-imidazo[1,2-b]pyridazin-6-yl]-amine (100 mg, 65%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.62-8.68 (m, 1H), 8.13-8.20 (m, 2H), 8.02 (dd, J=8.8, 1.5 Hz, 1H), 7.94 (d, J=9.9 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.21 (d, J=9.9 Hz, 1H), 3.43 (t, J=7.2 Hz, 2H), 1.66-1.79 (m, 2H), 1.49 (dq, J=15.1, 7.4 Hz, 2H), 0.99 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 307.2 [(M+H)+, calcd for C17H19N6 307.2].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:7]=1.[H-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:18]1([S:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([C:2]3[N:3]([S:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:34])=[O:33])[CH:4]=[CH:5][N:1]=3)=[CH:7]2)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ncc[nH]2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccnc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a solution of 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9ya) (20 mmol) in anhydrous THF (300 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.2 equiv, 24 mmol) and stirred for 20 min. Benzenesulfonyl chloride (1.2 equiv, 24 mmol) was added and the reaction mixture was stirred overnight. After dilution by 200 mL of saturated NaHCO3 solution (aqueous), the reaction mixture was extracted by ethyl acetate (600 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 5:1) to give a white solid. Yield: 40%. 1H NMR (CDCl3, 300 MHz) δ 8.02-8.08 (m, 4H), 7.72 (d, J=1.5 Hz, 1H), 7.35-7.60 (m, 8H), 7.23 (d, J=1.5 Hz, 1H), 7.10-7.16 (m, 3H). MS (ESI) calcd for C23H17N3O4S2 463.1. found 486.0 [M+Na]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)C>CCOC(C)=O>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][N:21]([C:16]2[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[CH:14][N:15]=2)[CH2:22][CH2:23]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cn2)CC1

Procedure:
5′-(4-tert-Butyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from N-(4-tert-butyl-phenyl)-6-chloro-nicotinamide and ethyl isonipecotate following a procedure similar to the one described in the synthesis of 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester above. The product was isolated by silica gel column purification with 20-30% EtOAc in hexanes gradient. HRMS m/z calcd for C24H31N3O3 [M+H]: 410.2438. Found: 410.2439.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].[CH2:11](O)C.CI>C(OCC)C>[CH3:11][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: CCO
Reactant: Oc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CCOCC
Product: COc1ccccc1Br
Temperature: 25 °C

Procedure:
Into a three-necked flask of 1liter, 25g (0.145 mol) of o-bromophenol, 6.1 g (0,152mol) of sodium hydroxide and 300 ml of ethanol were charged and refluxed for two hours. Then, 82.0 g (0.578 mol) of methyl iodide was added dropwise and the mixture was refluxed further for four hours. After the mixture was cooled to room temperature, 600 ml of diethyl ether was added. The mixture was charged into a separatory funnel. Separated organic layer was washed successively with, 100 ml of 2N-hydrochloric acid cooled with ice, 300 ml of saturated sodium thiosulfate, and water until the washings were neutral. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The concentrate was distilled under reduced pressure to obtain 25.3 g (0.135 mol) of o-methoxyphenylbromide.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[N:13][C:14]=2[CH3:16])[CH:9]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:8][CH:7]1[CH2:34][CH3:35])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:43]([O:45][CH3:46])=[O:44]>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[N:13][C:14]=2[CH3:16])[CH:9]([N:18]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:21]=2)[C:43]([O:45][CH3:46])=[O:44])[CH2:8][CH:7]1[CH2:34][CH3:35])=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N1c2c(cc(C)nc2C)C(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)N1c2c(cc(C)nc2C)C(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)CC1CC

Procedure:
This compound can be prepared by reacting, a solution of 4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6,8-dimethyl-3,4-dihydro-2H-[1,7]naphthyridine-1-carboxylic acid ethyl ester in THF and K2CO3 (2 to 5 eqv) with methyl chloroformate, followed by a typical workup procedure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([CH2:11][S:12][CH3:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C>[C:1]([C:5]1[CH:10]=[C:9]([CH2:11][S:12][CH3:13])[C:8]([O:14][CH3:15])=[C:7]([CH:6]=1)[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(CSC)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1c(N)cc(C(C)(C)C)cc1CSC

Procedure:
A mixture of 1.00 g 5-tert-butyl-2-methoxy-1-methylsulphanylmethyl-3-nitro-benzene, 4.20 g tin dichloride dihydrate and 15 ml of ethanol is refluxed for 2 h. Then the solvent is removed, and water and dichloromethane are added to the residue. The mixture is filtered through Celite, and the aqueous part of the filtrate is separated off and extracted twice with dichloromethane. The combined organic phases are dried (Na2SO4), and the solvent is removed. The residue is chromatographed on aluminium oxide with cyclohexane/ethyl acetate (4:1→1:4) as eluant.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1C=CC=CC=1>[Cl:15][CH2:16][C:17]([N:3]1[CH:4]([CH3:7])[CH2:5][CH2:6][CH:2]1[CH3:1])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: CC1CCC(C)N1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1CCC(C)N1C(=O)CCl
Reaction time: 0.25 h

Procedure:
A solution of 2,5-dimethylpyrrolidine (15 grams; 0.15 mol) and triethylamine (15 grams) in benzene (150 ml) was charged into a 250 ml glass reaction flask equipped with stirrer, reflux condenser and addition funnel. Chloroacetyl chloride (18 grams; 0.15 mol) was then slowly added, with vigorous stirring, over a period of several minutes. After the addition was completed stirring was continued for about 15 minutes. After this time the reaction mixture was filtered to remove the triethylamine hydrochloride which had formed. The filtered reaction mixture was then stripped of benzene under reduced pressure to yield a dark colored oil. The oil was distilled under vacuum to yield 1-(α-chloroacetyl)-2,5-dimethylpyrrolidine as a colorless oil having a boiling point of 89° to 90° C. at 0.1 mm of mercury pressure, and a refractive index at 25° C. of 1.4863.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 73.8 %

Procedure:
To a solution of 1.21 g (5.00 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.79 ml (20.0 mmol) of triethylamine in 50 ml of methylene chloride was added 1.65 ml (6.00 mmol) of palmitoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.50 g of the desired compound (73.8%, colorless powder), mp: 84.0°-85.0° C.