Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[N:7]=[C:6]([C:19]([OH:21])=O)[CH:5]=1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1>>[NH:28]1[C:27]([NH:26][C:19]([C:6]2[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[N:7]=2)=[O:21])=[N:31][N:30]=[N:29]1
Reactant: Nc1nnn[nH]1
Reactant: CC(C)c1cc(C(=O)O)nc(-c2ccc([N+](=O)[O-])cc2)c1
Solvent: O=S(Cl)Cl
Product: CC(C)c1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 42.5 %

Procedure:
In the same manner as described in Example 13-(1), 4-isopropyl-6-(4-nitrophenyl)-2-pyridinecarboxylic acid (1.62 g), thionyl chloride (15 ml) and 5-aminotetrazole (0.63 g) are reacted to give N-(5-tetrazolyl)-4-isopropyl-6-(4-nitrophenyl)-2-pyridinecarboxamide (0.85 g). M.P. 270°-272° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[O:6]1[C:17]2[C:9](=[CH:10][C:11](=[CH:15][CH:16]=2)[CH2:12][CH:13]=[CH2:14])[O:8][CH2:7]1.[ClH:18]>C(OCC)(=O)C>[Cl:18][CH:13]([CH3:14])[CH2:12][C:11]1[CH:15]=[CH:16][C:17]2[O:6][CH2:7][O:8][C:9]=2[CH:10]=1
Reactant: Cl
Reactant: C=CCc1ccc2c(c1)OCO2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(Cl)Cc1ccc2c(c1)OCO2

Procedure:
5 g of anhydrous tin chloride was added to 100 g of safrole. Hydrochloric acid gas was passed though the mixture under cooling with ice for 1.5 hours. 2 l of ethyl acetate was added to the reaction mixture, followed by the dissolution. The obtained mixture was washed with water twice, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane/benzene=10:1) to obtain 41.7 g of 5-(2-chloropropyl)-1,3-benzodioxole as a colorless oil. This oil was dissolved in 150 ml of ethanol, followed by the addition of 48 g of thiourea. The obtained mixture was heated under reflux for 7 days, cooled and filtered. A solution of 12.8 g of sodium hydroxide in 100 ml of water was added to the filtrate. The obtained mixture was heated under reflux for 2 hours, cooled and acidified with dilute sulfuric acid. 1 l of benzene and 1 l of water were added to the mixture to carry out the phase separation. The benzene layer was washed with water twice, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (hexane/benzene=10:1) to obtain 8.5 g of the title compound as a colorless oil.
Reaction SMILES: [O-2].[Mg+2:2].[C:3]([OH:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1>C(O)C>[C:3]([O-:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Mg+2:2].[C:3]([O-:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1
Reactant: O=C(O)c1cccnc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCO
Product: O=C([O-])c1cccnc1
Reaction time: 2 h
Yield: 98.9 %

Procedure:
8 grams (0.2 Mole) of magnesium oxide, 49.2 grams (0.4 Mole) of nicotinic acid and 150 ml ethanol were placed into a beaker provided with a reflux condenser. The mixture was stirred and boiled at atmospheric pressure for 2 hours. The mixture was cooled and thereafter filtered yielding 53.1 grams of magnesium nicotinate in the form of a fine white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH:18](O)[CH3:19])=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[N:6][CH:7]=1.FC1C=C(B(O)O)C=NC=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:43]=[N+:44]=[N-:45].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:43]([CH:18]([C:9]1[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH3:19])=[N+:44]=[N-:45]
Reactant: CC(O)c1ccc2cccnc2c1-c1cncc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: OB(O)c1cncc(F)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[8-(5-fluoropyridin-3-yl)quinolin-7-yl]ethanol (0.135 g, 0.503 mmol) (prepared in analogy to Example 7 step 1-4, using 5-fluoropyridin-3-ylboronic acid instead of (2-fluorophenypboronic acid as starting material) in methylene chloride (3 mL) was added triethylamine (0.105 mL, 0.755 mmol), followed by methanesulfonyl chloride (0.0487 mL, 0.629 mmol). After stirring at room temperature for 30 minutes, the resultant mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, then concentrated to dryness under reduced pressure. The crude mesylate was dissolved in N,N-dimethylformamide (2 mL) and treated with sodium azide (0.164 g, 2.52 mmol) at room temperature overnight. After diluting with ethyl acetate, the mixture was washed with water and brine, dried over magnesium sulfate and then evaporated to dryness. The crude product was used in the next step. LCMS calculated for C16H13FN5(M+H)+: m/z=294.1; found: 294.0.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([OH:11])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][N:3]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[C:17]([Si:21]([CH3:24])([CH3:23])[O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH3:1])=[N:3][NH:4]2)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1n[nH]c2cccc(O)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1n[nH]c2cccc(O[Si](C)(C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
To a solution of 3-methyl-1H-indazol-4-ol (0.13 g, 0.90 mmol) in N,N-dimethylformamide (10 ml) was added imidazole (0.31 g, 4.52 mmol) and tert-butyldimethylchlorosilane (0.16 g, 1.04 mmol) at 0° C. Following stirring at room temperature for 12 hours and the addition of distilled water (10 ml), the reaction mixture was extracted three times with ethyl acetate, washed with distilled water and brine, dried over magnesium sulfate, filtered, and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give 0.21 g of 4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-1H-indazole (Yield 89%).
Reaction SMILES: C[Si](C)(C)[Br:3].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21]>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Br:3])=[CH:10][C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: COCCCOc1cc(CO)ccc1OC
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: COCCCOc1cc(CBr)ccc1OC

Procedure:
97 ml of trimethylbromosilane are added, with stirring at room temperature, to 113.1 g of 4-methoxy-3-(3-methoxypropyloxy)-benzyl alcohol in 1.31 liters of chloroform. After 10 minutes the solvent is evaporated off and the residue is immediately purified by means of FC (900 g of silica gel, eluant: ethyl acetate/hexane 1:3). The title compound is obtained: Rf (ethyl acetate/hexane=1:2)=0.34; m.p. 50°-51° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+]>O>[C:4]([CH2:3][CH2:2][S:9]([O-:12])(=[O:11])=[O:10])([O:6][CH2:7][CH3:8])=[O:5].[Na+:13]
Reactant: CCOC(=O)CCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCS(=O)(=O)[O-]
Yield: 152.8 %

Procedure:
A mixture of 52 g (0.29 moles) ethyl 3-bromopropionate and 36.1 g (0.29 moles) anhydrous sodium sulfite in 150 ml water was refluxed for about 16 hours. The reaction mixture was stripped. The residue was washed with acetone and ethyl ether, stripped, and dried in a vacuum oven to give 90.5 g of the above-identified product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:16]([O:9][C:4]1[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc(Br)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
5-Bromo-2-chloro-pyridin-3-ol (500 mg, 2.399 mmol) and Cs2CO3 (1.2 g, 3.68 mmol) were combined in DMF (10 mL) at RT. To this was added benzyl bromide (0.34 mL, 2.86 mmol). After stirring overnight the mixture was diluted with H2O and extracted with Et2O (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-50 g, 0-10% EtOAc/hexanes) gave the title compound (674 mg, 94%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.07 (d, J=2.0 Hz, 1 H); 7.53-7.35 (m, 6 H); 5.16 (s, 2 H). LC/MS (M+H)+ 298/300/302.
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[C:4]2[N:15]=[CH:16][NH:17][CH2:18][C@@H:19]([OH:20])[C:3]=2[N:2]=1.NC1N([C@@H]2O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H]2OC(=O)C)C=NC=1C(O)=O>>[C@@H:6]1([N:5]2[C:4]3[N:15]=[CH:16][NH:17][CH2:18][C:19](=[O:20])[C:3]=3[N:2]=[CH:1]2)[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]1[OH:14]
Reactant: OC[C@H]1O[C@@H](n2cnc3c2N=CNC[C@H]3O)[C@H](O)[C@@H]1O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: O=C1CNC=Nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Another method also known for the synthesis of coformycin comprises preparing and using 5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxylic acid as a starting material which is processed by multi-stage reactions to produce 3-(β-D-ribofuranosyl)-6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one as an intermediate, followed by reducing the intermediate (see H. J. Thomas et al., "Nucleosides & Nucleotides", 5, No. 4, pp. 431-439, 1986).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)=[C:25]([F:39])[CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[C:31](=[CH:20][C:3]2[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=2[CH3:1])[C:32](=[O:38])[NH:33]3)=[C:25]([F:39])[CH:24]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2F)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4F)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 44.2 %

Procedure:
The title compound was prepared under the same conditions as described, in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(4-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(4-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (45 mg, 44.2%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:16])[NH:7][C:8]([NH:12][N+]([O-])=O)=[N:9][C:10]=1[CH3:11])[CH:2]([CH3:4])[CH3:3].[C:17](O)(=O)[CH3:18].C(N)C>O>[CH2:17]([NH:12][C:8]1[NH:7][C:6](=[O:16])[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([CH3:11])[N:9]=1)[CH3:18]
Reactant: Cc1nc(N[N+](=O)[O-])[nH]c(=O)c1CC(C)C
Reactant: CC(=O)O
Agent: CCN
Solvent: O
Product: CCNc1nc(C)c(CC(C)C)c(=O)[nH]1
Temperature: 120 °C

Procedure:
5-Isobutyl-6-methyl-2-nitraminopyrimid-4(3H)-one (16.0 g) was mixed with ethylamine acetate (30 g) and heated without solvent at 120° C for 6 hours. The melt was cooled and water was added. The mixture was brought to pH 5 and the precipitated product recrystallised from aqueous acetone to give 2-ethylamino-5-isobutyl-6-methylpyrimid-4(3H)-one (formula VII, R1 = CH3, R = is C4H9, R6 = H, R7 = C2H5) having a melting point of 203°-204° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>ClCCl>[CH3:31][S:32]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([C:20]([O:22][CH3:23])=[O:21])[CH2:3]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of crude (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (86.1 g) in dichloromethane (1 liter) under ice cooling are added triethylamine (52 ml) and then methanesulfonyl chloride (21.6 ml), and the mixture is stirred for 25 minutes. The reaction mixture is acidified with diluted hydrochloric acid and stirred. The organic layer is taken, washed with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and concentrated in vacuo to give (2S, 4R)-4-methanesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (2:90.0 g) as an organge oil. This product can be used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5](SC2C=CC=CC=2)[CH2:4][CH:3]1[CH2:16][CH:17]=[CH2:18].C(=O)([O-])[O-].[Ca+2].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[CH3:1][C@@H:2]1[CH2:7][C:6](=[O:8])[CH:5]=[CH:4][C@H:3]1[CH2:16][CH:17]=[CH2:18]
Reactant: C=CCC1CC(Sc2ccccc2)C(=O)CC1C
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1
Product: C=CC[C@@H]1C=CC(=O)C[C@H]1C
Yield: 52 %

Procedure:
A mixture of 96.7 nmole of 5-methyl-4-(2-propenyl)-2-phenylsulfenylcyclohexanone and 10 g. (100 mmole) of calcium carbonate in 300 ml. of toluene was heated at 110° C. for 40 minutes. The reaction was cooled, magnesium sulfate added and filtered. The filtrate was evaporated and the residue purified via column chromatography on 300 g. of silica gel eluted with 20% ether-hexane and then distillation to yield 7.61 g. (52%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]=[C:10]([C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])[NH:11][C:7]=2[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1.CCOCC>[CH3:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([CH2:3][OH:2])[CH:21]=[CH:20][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(C)cccc3C)[nH]c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1-c1nc2ccc(CO)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester (930 mg) (Example 1-255, step 1) in THF (10 mL) was added 16.6 mL of a 1M solution of LiAlH4 in ether dropwise. The mixture was stirred at ambient temperature for 18 h then approximately 4 mL of saturated sodium sulfate solution was added dropwide. Ethyl acetate was added to the mixture and the solvent decanted from any insoluble material. The organic solution was dried over sodium sulfate and the solvent was removed under reduced pressure to give [2-(2,6-dimethylphenyl)-3H-benzoimidazol-5-yl]-methanol as a foam.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C(COC)OC.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1cc(N2CCCC2)c2ccc(-c3cccc(Cl)c3)cc2n1
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
A mixture of 1.5 g 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline (Example 3.1), 256 tetrakis(triphenylphosphine) palladium and 30 ml Dimethoxyethane is stirred under argon for 15 min. 1.04 g 3-Chlorophenylboronic acid and 7 ml Ethanol are added. The resulting red solution is stirred for another 10 min. at room temperature and treated afterwards with 19 ml of a 2M aqueous solution of sodium carbonate. The mixture is refluxed for 1.5 h under vigorous stirring. After the reaction is complete, the reaction mixture is concentrated on a rotary evaporator. The residue is taken up in 50 ml water and extracted twice with 50 ml ethyl acetate. The combined organic phases are washed with 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. The filtrate is evaporated and the residue is chromatographed on silica gel (eluent: Dichloromethane/Methanol 19:1 then 4:1). The pure fractions are combined and evaporated. 1.235 g of 7-(3-Chloro-phenyl)-2-methyl-4-pyrrolidin-1-yl-quinoline are obtained as a colorless oil. MS (ISP): 323.3 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:7]=[CH:6][N:5]=1.[SH:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.[OH-].[Na+]>C(O)C>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:17][C:18]2[S:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[C:9]=1[CH3:10]
Reactant: COCCCOc1ccnc(CCl)c1C
Reactant: Sc1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1ccnc(CSc2nc3ccccc3s2)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.9 %

Procedure:
A mixture comprising 0.8 g of 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride, 0.5 g of 2-mercaptobenzothiazole, 0.36 g of sodium hydroxide and 30 ml of ethanol was stirred at a room temperature for 6 hours and distilled under a reduced pressure to remove the ethanol. The residue was purified by silica gel column chromatography to obtain 0.85 g of the title compound as a pale yellow crystal.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[CH2:37][O:36][CH3:33])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f4) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]([O:24]CC)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].Cl>ClCCCl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]([OH:24])=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28]
Reactant: CCOC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: Cl
Solvent: ClCCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CC(=O)O)c3c2)c1=O
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A mixture of ethyl 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetate (0.600 g), 10% hydrochloric acid (20.0 mL), and 1,2-dichloroethane (2.00 mL) is boiled for 30 minutes while allowing the 1,2-dichloroethane to evaporate, cooled, and poured onto ice. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a white solid (0.550 g, mp 240-242° C.).
Reaction SMILES: ClCCl.[I-].[C:5]([O:9][C:10]([N:12]([CH2:25][C@@H:26]1[C@@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][N:28]([C:37]([N:39]2[CH:43]=[CH:42][N+](C)=[CH:40]2)=[O:38])[CH2:27]1)[C@@H:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.N1CC[CH:55]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:54]C1>C(OCC)(=O)C>[C:5]([O:9][C:10]([N:12]([CH2:25][C@@H:26]1[C@@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][N:28]([C:37]([N:39]2[CH2:43][CH2:42][CH:55]([C:58]([O:60][CH2:61][CH3:62])=[O:59])[CH2:54][CH2:40]2)=[O:38])[CH2:27]1)[C@@H:13]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][CH:24]=1)[CH3:14])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)n2cc[n+](C)c2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CCNCC1
Agent: [I-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A 6.0 ml dichloromethane solution of 250 mg of 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}-3-methyl-1H-imidazol-3-ium iodide and 31 mg of triethylamine was mixed with 48 mg of ethyl 4-piperidine-carboxylate and stirred overnight at room temperature. The reaction solution was mixed with ethyl acetate and washed with water. The solvent was evaporated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 106 mg of ethyl 1-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}piperidine-4-carboxylate as a white amorphous substance.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>O1CCOCC1.CN(C)C=O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:13](=[O:14])[C:12]4[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:10]3=[O:15])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1cc(C2CC2)[nH]n1
Temperature: 120 °C

Procedure:
5-Cyclopropyl-1H-pyrazol-3-amine (5 g) was slurried in dioxane (80 mL) and N,N-dimethylformamide (80 mL), then phthalic anhydride (6 g) was added and the reaction was heated at 120° C. for 4 days. The reaction was cooled and concentrated. The crude material was triturated with isopropyl ether/ethanol 1/1 (30 mL) to provide the title compound.