Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=1.O>C(N)(CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC(=O)NC(C)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(C)N
Solvent: O
Product: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 45.5 mg (0.15 mmol) N-(1-(4-iodophenyl)propan-2-yl)acetamide (I52.1) and 27.3 mg (0.20 mmol) 1-chloro-4-ethynylbenzene in 750 μl sec-butylamine are added 14.3 (0.02 mmol) bis(triphenyphosphine)dichloropalladium (in 400 μl sec-butylamine) followed by 1.0 mL water. The reaction mixture is stirred at r.t. overnight. The solvent is removed in vacuo and the residue is purified by HPLC (ACN/H2O/TFA).
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:11][C:10]([CH3:13])([CH3:12])[O:9][C:8](=[O:14])[C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C:6]1[O:11][C:10]([CH3:12])([CH3:13])[O:9][C:8](=[O:14])[C:7]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(C)OC(=O)C(c2ccccc2)=C(CO)O1

Procedure:
6-Acetyloxymethyl-2,2-dimethyl-5-phenyl-2H,4H-1,3-dioxin-4-one (Compound No. 241, 7.46 g) was dissolved in methanol (108 ml), and cooled with ice; then, an aqueous solution (27 ml) of potassium carbonate (2.42 g) was added slowly thereto.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH3:19])[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11](N)=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1.[OH2:21]>>[OH:21][C:12]1[CH:13]=[C:14]2[C:9]([C:8]3[CH:16]=[CH:17][C:5]([CH:4]([CH3:19])[C:3]([OH:2])=[O:20])=[CH:6][C:7]=3[CH2:15]2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)Cc1cc(N)ccc1-2
Reactant: O
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cc(O)ccc1-2

Procedure:
The ester is dissolved in water (300 ml) containing concentrated HCL (11 ml) with the aid of heat. The solution is cooled to 3°, stirred and treated dropwise with a solution of sodium nitrite (2.84 g) in water (15 ml) over a 30 minute period. The resulting diazonium solution is then added dropwise over a 1 hour period to boiling water (800 ml) containing concentrated sulfuric acid (13 ml), and then stirred for 30 minutes and cooled. The precipitate is collected by filtration and heated in 10% aqueous potassium hydroxide containing charcoal for 1 hour, cooled and acidified with 4N HCl. The solid is collected by filtration to give 8.0 g, mp 205°-207° of the titled product. The analytical sample is prepared by sublimation, mp 218-219°.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]([N:9]([CH3:25])[C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7](=[O:8])[N:9]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:30]([CH2:28][CH3:29])[CH2:31][CH2:32][OH:33])[CH2:12][CH2:11]2)[CH3:25])=[CH:4][CH:3]=1
Reactant: CCNCCO
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Product: CCN(CCO)CCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to examples 31.6, trans-Methanesulfonic acid 4-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-butyl ester was treated with 2-ethylamino-ethanol to give trans-(4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butyl}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 411 (MH+, 1Cl).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(=O)(O)[O-].[NH4+].[N:34]1C=CC=CC=1>C(#N)C.O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:11](=[O:13])[NH2:34])[CH3:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC(NC(=O)OC(C)(C)C)C(N)=O
Reaction time: 12 h
Yield: 89.7 %

Procedure:
DL-N-Boc-alanine (5.0 g, 26.4 mmol), di-tert-butylpyrocarbonate (7.9 mL, 34 mmol), and ammonium bicarbonate (2.5 g, 32 mmol) were stirred together in acetonitrile (101 mL). Pyridine (1.3 mL, 16 mmol) was added. The mixture stirred for 12 hours. Water was added and then the acetonitrile was removed in vacuo. The resulting slurry was filtered. The solid was collected, dissolved in methylene chloride and methanol (90:10), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (2.7 g, 55%): 1H NMR (400 MHz, d6-DMSO): 7.20 (br s, 1H), 6.90 (br s, 1H), 6.77 (d, 1H), 3.86 (quintet, 1H), 1.37 (s, 9H), 1.15 (d, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH3:14])[S:8](=[O:16])(=[O:15])[C:7]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:6]1=2)(=O)[CH3:2]>O1CCCC1.CCOCC>[CH2:1]([NH:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH3:14])[S:8](=[O:16])(=[O:15])[C:7]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:6]1=2)[CH3:2]
Reactant: COCCC1CC(NC(C)=O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCNC1CC(CCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21

Procedure:
To a stirred solution of 4-acetamido-5,6-dihydro-6-(2-methoxyethyl)-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (4.4 g, 0.0115 mol) in tetrahydrofuran (45 ml) under nitrogen and heated to reflux was added borane dimethylsulfide complex (5 ml, 0.05 mol of a 10 M complex) over about 20 minutes. Stirring was continued at reflux for 3 hours, then at room temperature overnight and another 5 hours and then concentrated in vacuo at room temperature. Methanol (50 ml) was carefully added to the white residue. The resulting solution was saturated with anhydrous HCl gas and then was stirred at reflux for 1 hour. The solution was concentrated in vacuo and the residue was taken up in ethyl acetate (50 ml) and saturated sodium bicarbonate (20 ml). The ethyl acetate solution was separated and washed with saturated NaCl, dried, filtered and concentrated in vacuo. The procedure gave a mixture of cis and trans isomers (3.2 g) as a white gummy foam which was chromatographed on silica gel (300 g) using 7.5% methanol-chloroform. Mixed fractions (0.87 g) were chromatographed again using 5% methanol-ether. There was obtained 1.62 g of the a-isomer, mp 132°-134° C. and 0.35 g of the β-isomer, mp 167°-169° C. The hydrochloride salts of the α (trans) and β-isomer (cis) racemates were prepared using ethanolic-HCl and diluting with ether. MP's were 173°-175° C. and 264.5°-266° C., respectively.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:26][C:13]1[CH:14]=[N:15][C:16]([NH:18]C(=O)OC(C)(C)C)=[CH:17][C:12]=1[CH2:11]2.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[NH2:18][C:16]1[N:15]=[CH:14][C:13]2[CH2:26][C:3]3([CH2:11][C:12]=2[CH:17]=1)[C:4]1[C:5](=[N:6][CH:7]=[CH:8][CH:9]=1)[NH:10][C:2]3=[O:1]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A solution of (±)-tert-butyl (2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)carbamate from Step A (131 mg, 0.372 mmol) was stirred in CH2Cl2 (10 mL) and TFA (3 mL) for 18 h and then concentrated in vacuo to provide the title compound. MS: m/z=253 (M+1).
Reaction SMILES: C1(O[C:8](=[S:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:35][CH2:34]2)=[S:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=S)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 93 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([OH:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[OH:17])[CH3:2].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([O:16][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[O:17][CH2:14][CH2:15][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c(C(=O)OCC)cc1O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1cc(C(=O)OCC)c(OCCCCCC)cc1C(=O)OCC

Procedure:
15.0 g (59.0 mmol) diethyl-2,5-dihydroxyterephthalate, 20.0 ml (142 mmol) 1-bromohexane, 28.0 g (203 mmol) K2CO3 and 200 mg NaI in 100 ml acetone are heated under reflux for 66 hours. The initially yellow suspension becomes largely decolorized. The solvent is then distilled off and the residue is taken up in 400 ml ethyl acetate and 200 ml water. After removing the aqueous phase, the organic phase is washed three times with 80 ml 1 N NaOH and three times with 100 ml water and then dried over Na2SO4. After distilling off the ethyl acetate, the residue is taken up in petroleum ether. At -30° C., colourless crystals form which are recrystallized again from petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 3-thiopheneboronic acid according to the general procedure B. Obtained as a yellow solid (326 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C2C=CC=CC=2)[C@@:9]([NH:38]C(=O)OC(C)(C)C)([C:11]2[O:12][C:13]([C:16]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:19]=[C:18]([N:28]([CH2:34][CH2:35][O:36][CH3:37])[CH2:29][C@@H:30]4[CH2:32][C@H:31]4[CH3:33])[CH:17]=3)=[N:14][N:15]=2)[CH3:10])=[CH:4][CH:3]=1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[NH2:38][C@:9]([C:11]1[O:12][C:13]([C:16]2[CH:17]=[C:18]([N:28]([CH2:34][CH2:35][O:36][CH3:37])[CH2:29][C@@H:30]3[CH2:32][C@H:31]3[CH3:33])[N:19]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=2)=[N:14][N:15]=1)([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]
Reactant: COCCN(C[C@@H]1C[C@H]1C)c1cc(-c2nnc([C@](C)(NC(=O)OC(C)(C)C)C(c3ccccc3)c3ccc(F)cc3)o2)cc(N(C)S(C)(=O)=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(C[C@@H]1C[C@H]1C)c1cc(-c2nnc([C@](C)(N)Cc3ccc(F)cc3)o2)cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl [(1R)-2-(4-fluorophenyl)-1-(5-{2-{(2-methoxyethyl)[(trans-2-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]pyridin-4-yl}-1,3,4-oxadiazol-2-yl)-1-methyl-2-phenylethyl]carbamate (11.58 g, 17.9 mmol) in DCM (75 mL) cooled to 0° C. was added TFA (25 mL) and the reaction mixture was stirred at rt for 16 h, concentrated in vacuo, and reconcentrated several times from DCM, to give N-(4-{5-[(1R)-1-amino-2-(4-fluorophenyl)-1-methylethyl]-1,3,4-oxadiazol-2-yl}-6-{(2-methoxyethyl)[(trans-2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide as a TFA salt. MS M+1=547. 1H NMR (400 MHz, CD3OD) δ 7.10 (m, 5H), 7.01 (s, 1H), 3.82 (t, J=5.86 Hz, 2H), 3.64 (t, J=5.86, 2H), 3.50 (AB overlapping m, 4H), 3.39 (s, 3H), 3.35 (s, 3H), 3.18 (s, 3H), 1.88 (s, 3H), 1.05 (d, J=5.86, 3H), 0.78 (m, 2H), 0.49 (m, 1H), 0.30 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](Cl)=[O:13])=[C:5]2[Cl:15].[OH-].[NH4+:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH2:17])=[O:13])=[C:5]2[Cl:15]
Reactant: [NH4+]
Reactant: O=C(Cl)c1cnc2ccc(Br)cc2c1Cl
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)c1cnc2ccc(Br)cc2c1Cl
Yield: 95 %

Procedure:
DMF (1.506 mL, 19.37 mmol) was added to 6-bromo-4-oxo-1H-quinoline-3-carboxylic acid (51.93 g, 193.72 mmol) and thionyl chloride (353 mL, 4843.07 mmol) at r.t. and the resulting solution stirred at 70° C. for 2 h under an inert atmosphere. The resulting solution was evaporated to dryness and the residue azeotroped with toluene to afford 6-bromo-4-chloroquinoline-3-carbonyl chloride (62.13 g). The 6-bromo-4-chloroquinoline-3-carbonyl chloride was dissolved in DCM (420 mL) and added portionwise to ammonium hydroxide (251 mL, 1937.23 mmol) at 0° C. over 15 minutes. The organic solvent was removed under reduced pressure and the solid collected by filtration, washed with water, Et2O and then dried to afford the desired material (52.8 g, 95%) as a white solid. NMR Spectrum: 1H NMR (500 MHz, DMSO-d6) δ 8.00-8.11 (3H, m), 8.24 (1H, s), 8.45 (1H, s), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=287.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].C(=O)(O)[O-].[Na+].Br[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(#N)C>[C:7]([C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[CH2:3][N:2]([CH3:1])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])#[N:8]
Reactant: CNCc1cccc(C#N)c1
Reactant: CC(C)(C)OC(=O)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of 3-[(methylamino)methyl]benzonitrile (6.1 g, 41.7 mmol) and sodium bicarbonate (7.0 g, 83.4 mmol) in ACN (70 mL) was added dropwise tert-butyl 3-bromo-propanoate (7 mL, 41.7 mol). After being stirred at RT for 12 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica, pet ether/EtOAc) to afford the title compound as a pale yellow liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.70 (s, 2H), 7.60 (m, 1H), 7.51 (m, 1H), 3.49 (s, 2H), 2.58 (m, 2H), 2.36 (m, 2H), 2.09 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Li].Cl[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[F:32])(=[O:22])=[O:21]>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[F:32])(=[O:21])=[O:22]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: [Cl-]
Agent: [Li]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2F)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17.5 %

Procedure:
N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 2.34 g, 9.35 mmol, 0.95 eq) was suspended in THF (20 ml) and stirred at 0° C. for 10 minutes. 1,1,1,3,3,3-Hexanemethyldisilazane lithium salt (LiHMDS, 1M in THF, 19.5 ml, 20 mmol, 2.0 eq) was added dropwise maintaining the temperature below 30° C. and the reaction mixture stirred for a further 30 minutes. A solution of 4-(chlorosulfonyl)-3-fluorobenzoic acid (Preparation 9, 2.35 g, 9.85 mmol, 1 eq) in THF (15 ml) was added dropwise maintaining the reaction temperature below 30° C. and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with brine (10 ml), extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was slurried in t-butylmethyl ether and stirred at room temperature for 72 hours. The resulting solid was collected by filtration to yield the title compound as a beige solid (744 mg, 1.64 mmol, 17%).
Reaction SMILES: N#N.[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[CH:7]=[CH:6][N:5]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O>>[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH:13]=[CH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: O=Cc1ccccn1
Agent: N#N
Product: Nc1nccc(C=Cc2ccccn2)c1[N+](=O)[O-]
Yield: 49.9 %

Procedure:
Similarly to Example N2, the condensation of 2.58 g of 2-amino-4-methyl-3-nitropyridine and 1.8 g of pyridine-2-carbaldehyde gives 2.03 g of the title compound of m.p. 161–163° C. The mass spectrum shows the molecular peak MH+ at 243.0 Da.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([CH:15]=[CH:16][N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].CN([CH:28]=[O:29])C>>[CH:28]([C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:10]2=[N:17][CH:16]=1)=[O:29]
Reactant: CN(C)C=O
Reactant: c1ccc(COc2cccn3ccnc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnc2c(OCc3ccccc3)cccn12
Temperature: 10 °C

Procedure:
A mixture of 10 g of 8-(phenylmethoxy)imidazo[1,2-a]pyridine prepared in Example 13 and 31 ml of DMF is cooled to 10° C. 4.7 ml of POCl3 are added dropwise. The mixture is allowed to return to room temperature and then heated at 100° C. for 30 min. After cooling, 85 ml of H20 and 16 ml of NaOH (50%) are added. The mixture is heated at 90° C. for 1 h and then allowed to cool. The solid obtained is filtered off and then washed with water until the pH of the mother liquors is neutral. This gives 8.8 g of 3-formyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine.
Reaction SMILES: [C:1]([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:23]2[S:24][CH:25]=[C:26]([CH2:28][OH:29])[N:27]=2)[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>ClCCl>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][O:29][S:38]([CH3:37])(=[O:40])=[O:39])[N:27]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)S[C@H]1C[C@@H](c2nc(CO)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](c2nc(COS(C)(=O)=O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-(4-hydroxymethylthiazol-2-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.24 g) in dichloromethane (40 ml) was added triethylamine (2.1 ml) and methanesulfonyl chloride (1.2 ml) at 0° C. After stirring for 30 minutes at the same temperature, water (40 ml) was added thereto. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give (2S,4S)-4-acetylthio-2-[4-(methanesulfonyloxymethyl)thiazol-2-yl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.6 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:23])[CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:23])[CH2:15][S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CSc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenylsulfanyl-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](N)=[N:4][C:2]1=[O:3].[CH3:9][Si:10]([CH3:17])([CH3:16])[NH:11][Si:12]([CH3:15])([CH3:14])[CH3:13].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>>[CH3:9][Si:10]([N:11]([Si:12]([CH3:15])([CH3:14])[CH3:13])[C:8]1[CH:7]=[CH:5][NH:4][C:2](=[O:3])[N:1]=1)([CH3:17])[CH3:16]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Temperature: 10 °C

Procedure:
To 5.9 g of cytosine were added 112 ml of hexamethyldisilazane and 25 mg of ammonium sulfate. The solution was heated to 120° C.-125° C. for 3 hours with stirring and the excess hexamethyldisilazane was subsequently removed. The resulting solid residue was reconstituted in 35 ml of dichloromethane and cooled to 10° C. to form a homogenous bis-trimethylsilylcytosine solution.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:35]=[CH:36][CH:37]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:34][CH2:33][CH2:32][CH2:31][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)=[O:20])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:38]([N:40]([CH2:48][CH3:49])[C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1)[CH3:39].CCN=C=NCCCN(C)C.[ClH:61].C1C=CC2N(O)N=NC=2C=1.Cl.C(OCC)(=O)C>CO.O.C(Cl)Cl>[ClH:61].[ClH:61].[CH2:48]([N:40]([CH2:38][CH3:39])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:26]([C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]([C:18]3[C:17]4[CH2:31][CH2:32][CH2:33][CH2:34][C:16]=4[S:15][C:14]=3[NH:13][C:11](=[O:12])[C:10]3[CH:35]=[CH:36][CH:37]=[C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:9]=3)=[O:20])=[CH:23][CH:24]=2)=[O:28])=[CH:43][CH:42]=1)[CH3:49]
Reactant: O=C(O)c1ccc(NC(=O)c2c(NC(=O)c3cccc(CN4CCOCC4)c3)sc3c2CCCC3)cc1
Reactant: CCN(CC)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)c1ccc(NC(=O)c2ccc(NC(=O)c3c(NC(=O)c4cccc(CN5CCOCC5)c4)sc4c3CCCC4)cc2)cc1

Procedure:
A mixture of 150 mg of 4-{[(2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}benzoic acid, 57 mg of N,N-diethyl-p-phenylenediamine, 61 mg of WSC.hydrochloride, 42 mg of HOBt, and 1.5 mL of methylene chloride was stirred for 3 hours at room temperature. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by basic silica gel column chromatography (2% methanol/chloroform), thereby obtaining an oily material. Methanol and 4.0 M hydrogen chloride/ethyl acetate solution were added to this material, and the solution was concentrated under reduced pressure. The residue was treated with ethyl acetate, thereby obtaining 85 mg of N-(4-{[4-(diethylamino)phenyl]carbamoyl}phenyl)-2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide dihydrochloride.