Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH:22]=O)=[CH:9][CH:8]=1.C(O)=O.[OH-].[Na+].[CH:30]([NH2:32])=[O:31]>O>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][NH:32][CH:30]=[O:31])=[CH:9][CH:8]=1
Reactant: CN(C)CCCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CN(C)CCCNc1ccc(CNC=O)c2sc3ccccc3c(=O)c12
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 1-[[3-(dimethylamino)propyl]amino]-9-oxothioxanthen-4-carboxaldehyde (3.6 g; 10.57 mmol) in 50 mL of formamide containing 3.6 g of formic acid was refluxed for 1.5 h and then was allowed to stand at room temperature overnight. The reaction mixture was diluted with water (400 ml), basified with 3 mL of 5N NaOH solution, stirred rapidly for 30 rain, and the precipitated solid was filtered, washed with water, and dried, yielding 3.1 g (79%) of N-[[1-[[3-(dimethylamino)propyl]amino]-9-oxothioxanthen-4-yl]methyl]formamide (Formula I: R1 =R2 =Me; Q=CH2NHCHO; R8 =H; n=3), as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.Cl.Cl.[CH3:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:23][CH2:22]2)[CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:30][CH2:29][N:28]([CH2:27][CH:24]3[CH2:25][CH2:26][N:21]([C:19]4[CH:18]=[CH:17][N:16]=[C:15]([CH3:14])[N:20]=4)[CH2:22][CH2:23]3)[CH2:33][CH2:32]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1nccc(N2CCC(CN3CCNCC3)CC2)n1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nccc(N2CCC(CN3CCN(C(=O)c4ccc(F)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-fluorobenzoyl chloride(238 mg) in methylene chloride (5 ml) was added dropwise over 5 minutes to a mixture of 4-[-1-(2-methylpyrimidin-4-yl)-4-piperidylmethyl]piperazine trihydrochloride (625 mg) and triethylamine (1.04 ml) in dichloromethane (20 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1-2% methanol in dichloromethane. Filtration from ether gave 1-(4-fluorobenzoyl)-4-[1-(2-methyl-4-pyrimidinyl)-4-piperidylmethyl]piperazine, as a solid (244 mg), mp 127-128° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3Cl)[CH2:7]1)(=[O:3])[CH3:2].[Na+].[I-:27].FC(F)(F)C(O)=O>CC(=O)CC>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[I:27])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCC(C)=O
Product: CC(=O)OC[C@H]1C[C@@H](n2cnc3c(I)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of [(3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl acetate (185 mg, 0.45 mmol) in 2-butanone (8 mL) at 0° C. was added NaI (1.36 g, 9.08 mmol) followed by trifluoroacetic acid (174.8 μL, 2.27 mmol). The reaction was stirred for 3 hours at 0° C., quenched with saturated aq NaHCO3 and extracted with DCM. The organic phase was concentrated and the residue was purified by flash chromatography (0 to 100% EtOAc/DCM) to obtain the title compound (140 mg, 67%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2>>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[CH:1][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1ccc2c(c1)CCO2
Product: O=C1Nc2ccc(Br)cc2C1=Cc1ccc2c(c1)CCO2

Procedure:
2,3-Dihydro-5-formylbenzofuran (commercially available) was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(2,3-dihydrobenzofuran-5-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[C:27]([N:29]4[C:37]5[C:32](=[CH:33][C:34]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:36]=5)[CH2:31][CH2:30]4)[N:26]=[CH:25][N:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[C:27]([N:29]4[C:37]5[C:32](=[CH:33][C:34]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][CH:36]=5)[CH2:31][CH2:30]4)[N:26]=[CH:25][N:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)N2CCC(Oc3cc(N4CCc5cc(S(C)(=O)=O)ccc54)ncn3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCNC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
21a was dissolved in 2.5 mL of DCM and 2.5 mL of TFA was added. The mixture was stirred at room temperature for 2 h then evaporated and the crude material was dissolved in DCM, washed with saturated NaHCO3 (3×10 mL), dried, filtered and evaporated to afford 21b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([N:23]([CH3:27])[CH2:24][CH2:25][OH:26])[CH:20]=[C:19]([CH3:28])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([N:23]([CH3:27])[CH2:24][CH2:25][OH:26])[CH:20]=[C:19]([CH3:28])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(N(C)CCO)nc(Cl)n1
Product: COc1cc(Nc2nc(C)cc(N(C)CCO)n2)ccc1-n1cnc(C)c1
Yield: 57 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-[(2-chloro-6-methyl-pyrimidin-4-yl)-methyl-amino]ethanol. The title compound was isolated as a colorless solid in a yield of 57%. MS ISP (m/e): 369.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.70 (d, 1H), 7.60 (s, 1H), 7.11 (d, 1H), 7.05-6.90 (m, 2H), 6.85 (s, 1H), 5.92 (s, 1H), 3.95-3.80 (m, 2H), 3.84 (s, 3H), 3.80-3.70 (m, 2H), 3.12 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: Cl.Cl.[C:3]1([CH2:9][O:10][NH:11][CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][NH:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[O:29]=[C:30](Cl)OC(Cl)(Cl)Cl.CN(C1C=CC=CN=1)C>C(#N)C>[C:3]1([CH2:9][O:10][N:11]2[CH:12]3[CH2:13][N:14]([NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=43)[C:30]2=[O:29])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(CONC2CNNc3ccccc32)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1N2CC(c3ccccc3N2)N1OCc1ccccc1
Reaction time: 1 h
Yield: 135.7 %

Procedure:
3.13 g of the compound obtained in stage C are dissolved in 1.9 l of acetonitrile. 4.81 g (6.6 ml) of triethylamine are added dropwise over 10 minutes. 0.943 g (575 μl) of diphosgene is subsequently added slowly at 0° C., followed by 1.27 g of dimethylaminopyridine. The temperature is subsequently allowed to return to ambient temperature. After one hour, the acetonitrile is evaporated and the residue is treated with NaH2PO4 (1M aqueous solution). Extraction is carried out with a heptane/AcOEt 1:2 mixture and washing is carried out with water. The organic phase is dried over MgSO4 and evaporated to dryness. This residue is crystallized from ether at 0° C. 1.82 g of the expected compound (68%) are obtained.
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:10][C@H:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12])[C:3]=1[C:4]#[N:5].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:21]([C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:10][C@H:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12])[C:3]=1[C:4]#[N:5])=[N+:22]=[N-:23]
Reactant: C[C@@H](CCc1ccccc1)Nc1ccnc(Br)c1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](CCc1ccccc1)Nc1ccnc(N=[N+]=[N-])c1C#N
Yield: 87.7 %

Procedure:
Prepared according to the methods above using (S)-2-bromo-4-((4-phenylbutan-2-yl)amino)nicotinonitrile (76.1 mg, 0.230 mmol), sodium azide (30.0 mg, 0.461 mmol) and ammonium chloride (24.65 mg, 0.461 mmol) in DMF (1.0 mL) at 100° C. for 2.5 hours to give the desired product as a yellow oil (59 mg). LC/MS (291/293, [M−H]−/[M+H]+).
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.Br[CH:11]([CH2:14][CH2:15]Cl)[CH:12]=[O:13]>O>[CH:12]([C:11]1([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:15][CH2:14]1)=[O:13]
Reactant: O=CC(Br)CCCl
Reactant: CC(C)(C)S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)SC1(C=O)CC1
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen and while cooling with ice, 112 ml of tert-butyl mercaptan are added dropwise over 10 minutes to a solution, cooled to 5° C., of 80 g of sodium hydroxide in 750 ml of water. Then 50 ml of methanol are added. After 1 hour, 151 g of 2-bromo-4-chlorobutanal (89.5%) are added dropwise over 15 minutes with efficient stirring and cooling, whereupon the temperature of the reaction mixture rises from 5° to 20° C. After 30 minutes, the mixture is extracted 4 times with diethyl ether. The combined organic phases are washed twice with a saturated solution of sodium chloride and dried over magnesium sulfate. The residue obtained after concentrating the residue on a rotary evaporator is fractionated over a 30 cm packed column, affording 89 g of 1-formyl-1-tert-butylthiocyclopropane in 89% purity. Boiling point: 112°-114° C./8 400 Pa.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]2[C:25]3[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:24]=3[C:23]3[C:22]4[CH:21]=[C:20]([O:31]C)[CH:19]=[CH:18][C:17]=4[NH:16][C:15]=3[CH:14]=2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].Cl.[NH+]1C=CC=CC=1>>[N+:10]([C:8]1[CH:7]=[C:6]([C:13]2[C:25]3[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:24]=3[C:23]3[C:22]4[CH:21]=[C:20]([OH:31])[CH:19]=[CH:18][C:17]=4[NH:16][C:15]=3[CH:14]=2)[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)([O-:12])=[O:11]
Reactant: COc1ccc2[nH]c3cc(-c4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)c4c(c3c2c1)C(=O)NC4=O
Agent: Cl
Agent: c1cc[nH+]cc1
Product: O=C1NC(=O)c2c1c(-c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)cc1[nH]c3ccc(O)cc3c21
Yield: 57 %

Procedure:
The reaction of 4-(3,5-dinitrophenyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=3,5-dinitrophenyl, R10═H) (42) prepared as described in example 48 with pyridinium hydrochloride according to the proceedure described in example 81 gave 4-(3,5-Dinitrophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=3,5-dinitrophenyl, R10═H) (43) in a 57% yield as an orange powder, mp>330° C. 1H NMR δ [(CD3)2SO] 11.94 (br s, 1H), 11.18 (br s, 1H), 9.32 (br s, 1H), 8.91 (s, 3H), 8.35 (d, J=2.3 Hz, 1H), 7.83 (s, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.11 (dd, J=8.7, 2.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13]2([C:26]([O:28]C)=[O:27])[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>[OH-].[Na+].CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:13]2([C:26]([OH:28])=[O:27])[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
A heterogeneous mixture of 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-4-[carbomethoxy]-piperidine (1.2 g, 2.26 mmol) in 50% aqueous sodium hydroxide (10 mL) and methanol (50 mL) is heated to reflux for 16 hours. The methanol is evaporated and the residue is neutralized with 4N hydrochloric acid. The aqueous solution is extracted with ethyl acetate. The combined organic extracts are dried (NaSO4) and the solvent is evaporated to give 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-4-[carboxy]piperidine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 6.87 g (0.043 mol) of 4-trifluoromethylaniline in 110 ml of dichloromethane was added 5.25 ml (0.043 mol) of pivaloylchloride. After stirring for 1.5 hours, 190 ml of a saturated solution of aqueous sodium bicarbonate was added. The reaction proceeded an additional 2 hours and the organic layer was separated and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed to give the title compound, yield 9.16 g (88%), m.p. 154°-158° C.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:22])[NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=1)[CH2:2][CH3:3].Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][N:25]=1.N1CCOCC1>>[O:33]1[CH2:34][CH2:35][N:30]([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:22])=[CH:12][CH:11]=3)[N:29]=2)[CH2:31][CH2:32]1
Reactant: Clc1nccc(N2CCOCC2)n1
Reactant: CCCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: C1COCCN1
Product: CCCNC(=O)Nc1ccc(-c2nccc(N3CCOCC3)n2)cc1

Procedure:
Method as described for Example 34 using (4-(3-propylureido)phenyl)boronic acid pinacol ester and 4-(2-chloropyrimidin-4-yl)morpholine which was synthesised according to Intermediate 3, using morpholine as starting material.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][C@H:15]1[CH2:19][N:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C@H:17]([C:33]([O:35][CH3:36])=[O:34])[CH2:16]1>CN(C=O)C>[Si:1]([O:14][C@H:15]1[CH2:19][N:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C@H:17]([C:33]([O:35][CH3:36])=[O:34])[CH2:16]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 4 h
Yield: 93.6 %

Procedure:
t-Butyldimethylsilyl chloride (TBSCl) (4.07 g, 27.03 mmol) and imidazole (2.58 g, 37.8 mmol) were added to a solution of (3) (9.55 g, 27.03 mmol) in DMF (60 ml) at RT. The reaction was stirred for 4 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with 0.1M aqueous HCl, sat. sodium bicarbonate solution and brine. The organic layers were dried with sodium sulfate and concentrated in vacuo to yield (2S,4R)-methyl 4-(tert-butyldimethylsilyloxy)-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxylate (4) (11.83 g, 94%) as a yellow oil. It was used without further purification in the next step. MS m/z 490.2. (M+Na)+; retention time=3.159 min, method [1].
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([F:16])([F:15])[F:14])[CH:7]=1>S(=O)(=O)(O)O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([O:12][C:13]([F:14])([F:15])[F:16])[CH:7]=1
Reactant: Fc1cccc(OC(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)cc1OC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
Fuming nitric acid (20 mL) was added dropwise to concentrated sulfuric acid (40 ml) under cooling (−10° C.), and subsequently, 1-fluoro-3-(trifluoromethoxy)benzene (15 g, 83 mmol) was added to the mixture at −10° C., and the mixture was stirred for 0.5 hours. After the mixture was added into ice-water to stop the reaction, it was extracted with dichloromethane. After the obtained organic layer was washed with a 1N aqueous sodium hydroxide solution and water, it was dried with anhydrous sodium sulfate. After filtration, the solution was concentrated and the residue was purified by silica gel column chromatography (100:0-97:3, hexane:ethyl acetate) to give the title compound (3.1 g, 16%) as an oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)CCC>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4cccnc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
1-(β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzene obtained in Example 19 was used and treated in a manner similar to Example 106-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzene as colorless crystals. APCI-Mass m/Z 590/592 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzene and tri-n-butyl(3-pyridyl)tin were used and treated in a manner similar to Example 124 to give the target compound as colorless powder. APCI-Mass m/Z 448/450 (M+H).
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:27])[CH2:20]2.Cl>C1CCCCC1.O1CCCC1>[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([C:21]2([OH:27])[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: OC1(c2ccc(-c3ccccc3)cc2)CN2CCC1CC2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 41.1 %

Procedure:
A solution of sec-butyllithium in cyclohexane (100 ml, 1.3M) was added dropwise with stirring to a solution of 4-bromobiphenyl (25 g) in dry tetrahydrofuran (240 ml) under an argon atmosphere at -78° C. The mixture was stirred for 5 minutes and a solution of quinuclidin-3-one (12 g) in dry tetrahydrofuran (100 ml) added during 20 minutes. Stirring was continued at -78° C. for 30 minutes and the mixture allowed to reach room temperature over 2 hours. 2M Hydrochloric acid (225 ml) was added keeping the reaction temperature below 10° C. The aqueous layer was separated and washed with diethyl ether (2×300 ml) before the addition of excess sodium hydroxide solution (density 1.35 g/cm3) to pH14. The mixture was extracted with ethyl acetate which had been heated to 50° C. and the ethyl acetate phase separated, dried (Na2SO4) and evaporated to yield a colourless solid which crystallised from ethyl acetate to give 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (11.0 g) m.p. 165°-166° C.; microanalysis, found: C, 81.1; H, 7.5; N, 5.2%; C19H21NO 0.1H2O requires: C, 81.1; H, 7.5; N, 5.0%; NMR (CDCl3 /CD3CO2D): 1.7-1.9(3H, m,), 2.5(1H, m), 2.5-2.7(1H, m), 3.2-3.5(4H, m), 3.7(1H, dd), 4.0(1H, dd) and 7.3-7.7(9H, m); m/z 279 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9]1([CH2:15][N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:21][CH2:20]2)[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: CN1CCCN(C2CCN(Cc3ccccc3)CC2)CC1
Yield: 35 %

Procedure:
Prepared analogously to Example A11a) from hexahydro-1-methyl-1H-1,4-diazepine and 1-(phenylmethyl)-4-piperidinone in a yield of 35% of theory. Colourless viscous oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:3]1.CCN(C(C)C)C(C)C.[Cl:23][C:24]1[C:25]([C:31]#[N:32])=[N:26][CH:27]=[C:28](Cl)[N:29]=1>C1COCC1>[Cl:23][C:24]1[N:29]=[C:28]([NH:1][C@@H:2]2[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:3]2)[CH:27]=[N:26][C:25]=1[C:31]#[N:32]
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: CN(C)C(=O)N1CCCC[C@@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCCC[C@@H](Nc2cnc(C#N)c(Cl)n2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
(R)-3-Amino-N,N-dimethylazepane-1-carboxamide (508) (˜200 mg crude) was dissolved in THF (7 mL), and DIEA (0.30 mL, 1.7 mmol) was added, followed by 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.57 mmol). The reaction was stirred at RT for 12 hours. The solvents were removed under reduced pressure, and the residue was purified by silica column chromatography (MeOH, DCM) to give (R)-3-(6-chloro-5-cyanopyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide (509) (53 mg, 0.16 mmol, 14% yield over 3 steps).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl[CH2:11][C:12](=O)[CH3:13]>C(O)C>[CH3:13][C:12]1[N:9]=[C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[S:8][CH:11]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)c1cccnc1
Solvent: CCO
Product: Cc1csc(-c2cccnc2)n1
Reaction time: 48 h
Yield: 12.9 %

Procedure:
(See FIG. 10.) To a solution/slurry of thionicotinamide (3.3 g, 23.9 mmol) in ethanol (100 mL) is added chloroacetone (2.28 mL, 28.7 mmol) and the resultant slurry is heated to reflux and stirred for 48 h. The solvent was removed in vacuo and the crude material was chromatographed on silica gel (EtOAc/Hex, 50/50, Rf=0.34) to afford the title compound 26 (543 mg, 13% yield) as a brown solid: mp=42-43° C.; 1H NMR (CDCl3) δ 9.09 (m, 1H), 8.57 (m, 1H), 8.15 (m, 1H), 7.31 (m, 1H), 6.89 (m, 1H), 2.47 (s, 3E1); LRMS (ESI) calcd for C9H8N2S [M+H]+ 177. found 177.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].Cl.[CH3:18]O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:18])=[O:15]
Reactant: CO
Reactant: O=C(O)CCCCc1nc2ccccc2s1
Agent: Cl
Product: COC(=O)CCCCc1nc2ccccc2s1
Yield: 67 %

Procedure:
A solution of 5-(2-benzothiazolyl)pentanoic acid (1.54 g, 6.5 mmol, prepared according to the procedure of Example 12 in JP, A, 8-208631 (1996)) in hydrochloric acid-methanol (40 ml) was stirred at room temperature overnight, and evaporated. The residue was dissolved in chloroform, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, evaporated, and purified through flash column chromatography to give methyl 5-(2-benzothiazolyl)pentanoate (1.08 g, 67%).