Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH:30]2[CH2:38][CH3:39])=[O:28])[CH:22]=1.Cl>CC(O)C>[CH2:38]([CH:30]1[CH2:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]1[C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:17](=[CH:18][CH:19]=2)[CH2:16][C:6]2([C:14]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]2=[O:15])[CH2:5]3)[CH:22]=1)=[O:28])[CH3:39]
Reactant: CCC1Cc2ccccc2N1C(=O)c1cc(Cl)ncn1
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: Cl
Solvent: CC(C)O
Product: CCC1Cc2ccccc2N1C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1

Procedure:
103 mg (0.40 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 113 mg (0.40 mmol) (6-chloro-pyrimidin-4-yl)-(2-ethyl-2,3-dihydro-indol-1-yl)-methanone and 13 μL of a 4 molar aqueous hydrochloric acid solution were added to 2.0 mL of 2-propanol and the mixture was refluxed for 2 h. Then the reaction mixture was evaporated down and purified by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The residue was made alkaline with a 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:4]2[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[C:10]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:23]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>CN1C(=O)CCC1.CS(C)=O>[CH3:22][C:17]1[C:16]([C:10]2[C:11]([O:14][CH3:15])=[CH:12][C:13]3[C:4]4[N:3]([CH2:24][CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:2]([NH:34][CH2:33][CH2:31][OH:32])=[N:23][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n(CC3CCOCC3)c12
Reactant: NCCO
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCO)n(CC3CCOCC3)c12
Temperature: 180 °C
Yield: 5.4 %

Procedure:
2-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (for a preparation see Intermediate 15) (14 mg, 0.033 mmol) and ethanolamine (0.020 ml, 0.327 mmol) were dissolved in NMP (2 ml) and heated at 180° C. in the microwave for 1 h, then cooled and loaded onto a 10 g SCX-2 cartridge, washing with methanol (30 ml). The cartridge was then eluted with 2M methanolic ammonia (30 ml) and the eluant evaporated in vacuo to give a sparingly soluble brown gum. This was dissolved in DMSO (1 ml) and purified by MDAP (formate) to give 2-{[7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]amino}ethanol (0.80 mg, 1.772 μmol, 5.40% yield) as a pale yellow glass. LCMS (formate) Rt 0.62 min, MH+ 452
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH3:22])=[C:15]([C:18]([NH2:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)C=CC=CC=1.C(OCC)(=O)C.O>CS(C)=O.CO>[CH3:22][O:21][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([S:7][C:5]3[S:6][C:2]([NH:1][C:30]([NH:31][C:32]4[S:33][CH:34]=[CH:35][N:36]=4)=[O:29])=[CH:3][CH:4]=3)=[CH:9][CH:10]=[N:11]2)=[CH:16][C:15]=1[C:18]([NH2:20])=[O:19]
Reactant: COc1cc2nccc(Sc3ccc(N)s3)c2cc1C(N)=O
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc2nccc(Sc3ccc(NC(=O)Nc4nccs4)s3)c2cc1C(N)=O
Yield: 38.5 %

Procedure:
4-(5-Aminothiophen-2-ylsulfanyl)-7-methoxyquinoline-6-carboxamide (66.0 mg, 0.200 mmol) and thiazol-2-ylcarbamic acid phenyl ester (66.0 mg, 0.300 mmol) were stirred in dimethylsulfoxide (1 ml) at 85° C. for 2 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:methanol=15:1), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (35.0 mg, 0.077 mmol, 38%) as colorless crystals.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C=CC(OC)=C(C[OH:31])C=1)(C)(C)C.C(Br)(Br)(Br)Br.CCCCCCC>C(Cl)Cl>[C:14]1([P:7](=[O:31])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C(C)(C)C)cc1CO
Agent: BrC(Br)(Br)Br
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
Triphenyl phosphine (5.84 g, 22.3 mmol) was added to a solution of (5-tert-butyl-2-methoxyphenyl)methanol (4.20 g, 21.8 mmol) in anhydrous DCM (80 ml) and the mixture cooled to 10° C. Carbon tetrabromide (7.39 g, 22.3 mmol) was added with stirring over 10 min, and after 30 min the temperature was raised to ambient temperature. Stirring continued for 17.5 h when the solvent was lowered to 20 ml under reduced pressure. Addition of heptane (80 ml) with stirring resulted in precipitation of triphenyl phosphine oxide, which was removed by filtration of the mixture through dicalite. Evaporation of the filtrate gave a straw coloured gum, purification of which was achieved by chromatography on silica using heptane:DCM (1:1) as eluent to afford 2-bromomethyl-4-tert-butyl-1-methoxybenzene as a clear gum (2.02 g, 36%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][Cl:10])=[N:6][N:7]=1.[CH3:13][N:14]=[C:15]=[O:16]>C1C=CC=CC=1>[CH3:13][NH:14][C:15]([N:2]([CH3:1])[C:3]1[S:4][C:5]([C:8]([CH3:11])([CH3:12])[CH2:9][Cl:10])=[N:6][N:7]=1)=[O:16]
Reactant: CNc1nnc(C(C)(C)CCl)s1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N(C)c1nnc(C(C)(C)CCl)s1

Procedure:
To a stirred suspension of 6.0 g of 2-methylamino-5-(β-chloro-α,α-dimethylethyl)-1,3,4-thiadiazole in 100 ml of benzene was added 2.0 g of methyl isocyanate. The mixture became homogenous upon heating to reflux temperature and reflux was maintained for 2 hrs. After cooling, the benzene was removed at reduced pressure and the precipitate collected, giving 7.4 g (95%), m.p. 159°-161°. An analytical sample was prepared from methylene chloride-ether, m.p. 160°-161°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.CO>[Fe].O>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[NH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2ncc[nH]2)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CO
Product: Nc1ccc(Sc2ncc[nH]2)cc1N
Reaction time: 2 h

Procedure:
A mixture of 2.6 g. of 2-amino-4-(imidazol-2-ylthio)-1-nitrobenzene, 2.6 g. of iron powder and 1.3 g. ferrous sulfate in 200 ml. methanol and 50 ml. water is refluxed for 2 hours. An additional 2.6 g. of iron is added and refluxing continued for 2 hours. The mixture is filtered and the filtrate stripped to yield 1,2-diamino-4-(imidazol-2-ylthio)benzene.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>>[N:1]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCCC1c1cccnc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Product: CN1CCC[C@@H]1c1cccnc1

Procedure:
Several resolving agents, solvents and their combinations were studied to resolve the synthetically obtained racemic nicotine. When the naturally available d-tartaric acid was used as the resolving agent, only the unnatural (R)-nicotine was obtained with low chiral purity (62%). When l-tartaric acid was used (S)-nicotine was obtained. Although its chiral purity was high (98.3%), the yield was very low (29%). When di-p-toluoyl-d-tartaric acid was used, (S)-nicotine was obtained in 60% yield with 88% chiral purity. When di-p-toluoyl-l-tartaric acid was used, (R)-nicotine was obtained in 15% yield with 94.7% chiral purity. In all the above cases, either the yield or the chiral purity was not satisfactory. We also studied dibenzoyl-d-tartaric acid as a resolving agent in different solvents (Table.1).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[C:67]([O:71][C:72]([N:74]1[CH2:79][CH2:78][N:77]([C:80]2[CH:85]=[CH:84][C:83]([CH:86]=O)=[CH:82][CH:81]=2)[CH2:76][CH2:75]1)=[O:73])([CH3:70])([CH3:69])[CH3:68]>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:86]([C:83]3[CH:82]=[CH:81][C:80]([N:77]4[CH2:76][CH2:75][N:74]([C:72]([O:71][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:73])[CH2:79][CH2:78]4)=[CH:85][CH:84]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 30.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.13 mmol), DMF (0.3 mL), ethanol (1.2 mL), 1M Na2S2O4 (3 eq, 0.38 mmol, 0.38 mL) and 4-(4-formylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.1 eq, 0.14 mmol, 43 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (25 mg, 31%) as an off-white solid; δH (500 MHz, DMSO-d6) 1.43 (s, 9H, C(CH3)3), 2.61 (s, br, 4H, piperazine N(CH2)2), 3.26 (s, br, 4H, piperazine N(CH2)2), 3.48 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 3.61 (s, 2H, CH2), 3.64 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 7.06 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.6, 4.7 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.03 (d, J=8.9 Hz, 2H, phenyl H-2 & H-6), 8.17 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (dd, J=4.6, 1.5 Hz, 1H, pyridine H-6), 8.56 (d, J=1.4 Hz, 1H, pyridine H-2), 13.22 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:12])([CH3:11])[S:9][CH:8](O)[CH:5]2[O:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:12])([CH3:11])[S:9][CH:8]=[C:5]2[O:6][CH:7]=1
Reactant: CC1(C)SC(O)C2OC=C(Br)C=C21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)SC=C2OC=C(Br)C=C21
Temperature: 25 °C

Procedure:
A solution of 3-bromo-5,6-dihydro-7-hydroxy-5,5-dimethyl -7H-thieno[3,4-b]pyran (12.06 g, 45.8 mmol) and p-toluenesulfonic acid (0.26 g, 1.37 mmol) in benzene (300 mi) was heated to reflux for 3 h in an apparatus fitted with a Dean-Stark trap to remove water. The resultant solution was cooled to rt and filtered through a pad of silica gel and the silica gel was washed with dichloromethane; the organic solutions were combined. The solvent was evaporated in vacuo to give the product as a brown oil, 10.23 g (91%); 1H NMR (CDCl3): δ 1.38 (s,6H), 5.65 (d, J=14 Hz, 1H), 6.37 (d, J=14 Hz, 1H) and 6.87 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[Cl:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Cl:12][CH2:13][C:14]([C:2]1[S:1][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:15]
Reactant: O=C1NCCCc2ccsc21
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)c1cc2c(s1)C(=O)NCCC2
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 2 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 2 g of chloroacetyl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride. The mixture was stirred for 30 minutes, refluxed under heating for an hour and then poured into water. The precipitated crystals were collected by filtration and washed with isopropyl alcohol to give 2 g of 2-chloroacetyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one, m.p. 221°-223° C. (decomposition).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=3)[N:17]=1)[CH2:12]2)=O)(C)(C)C.FC(F)(F)C(O)=O.N>ClCCl>[CH:13]12[NH:8][CH:9]([CH2:15][CH2:14]1)[CH2:10][N:11]([C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=3)[N:17]=1)[CH2:12]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2nc(N3CC4CCC(C3)N4)ccc2c1
Reaction time: 15 h

Procedure:
A mixture of 3-(6-nitro-quinolin-2-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.0 g, 2.6 mmol), trifluoroacetic acid (2.97 g, 26.0 mmol) and dichloromethane (10 ml) was stirred for 15 h. The mixture was made alkaline by adding concentrated ammonia. The mixture was extracted with dichloromethane, dried and evaporated. Yield 0.50 g (90%) Mp 185° C. decomp.
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[CH:17]=[CH:16][C:15]([C:3]2[O:4][C:5]3[C:10]([C:11](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:14]1
Reactant: O=c1c(I)coc2ccccc12
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2cc[nH]n2)oc2ccccc12
Temperature: 0 °C
Yield: 70.8 %

Procedure:
To an eggplant type flask (20 ml), 3-iodochromone (136 mg) prepared in Example 1, pyrazole (136 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added and the mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and the purified compound was recrystallized from benzene/hexane to give the titled compound (75.1 mg; yield=70.8%) as white needle crystals. Melting point: 143°-144° C. 1 H-NMR(CDCl3, δ ppm): 6.90 (s, H3), 8.24 (dd, H5), 7.46-7.58 (m, H6), 7.76 (t, H7), 7.46-7.58 (m ,H8), 7.85 (d, H3'), 6.59 (dd, H4'), 8.23 (d, H5').
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15]([NH:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:30])=[CH:27][N:26]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccccc2)nc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)NCc2ccccc2)nc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to benzylamine via Procedure G. Crude methyl 6-(benzylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 300 mg of 6-(benzylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(benzylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N2-benzyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])(=[N:15][CH:12]2[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)Nc1ccc(Br)cc1
Reactant: NC1CC1
Product: CS(=O)(=NC1CC1)Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and cyclopropylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.93 min; Mass spectrum (ESI+): m/z=289, 291 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH2:7][C:8]([P:14]([OH:17])([OH:16])=[O:15])([P:10]([OH:13])([OH:12])=[O:11])[OH:9])[CH:2]=1.[OH-].[Na+:19]>O>[CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH2:7][C:8]([P:10]([O-:12])([OH:13])=[O:11])([P:14]([OH:17])([OH:16])=[O:15])[OH:9])[CH:2]=1.[Na+:19]
Reactant: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=P([O-])(O)C(O)(Cc1cccnc1)P(=O)(O)O

Procedure:
21.0 g of risedronic acid and 700 ml of deionized water are charged into a 1-liter reactor, equipped with mechanical stirrer and thermometer. The suspension, under stirring, is added with 148.4 ml of NaOH 0.5N thus obtaining complete dissolution of the suspended solid. The pH of the solution is 4.67. The solution is kept under stirring for 10′ and filtered on a paper filter and put into Lioguard chambers. The chambers are introduced into a lyophilizer which is set according to the following parameters: a) freezing-phase: temperature −40° C., freezing time 3 hours; b) lyophilization phase: time 89 hours, internal temperature 30° C., residual vacuum 400÷450 μHg. At the end of the process, the white and soft product is discharged from the chambers. 20.9 g of lyophilized amorphous sodium risedronate are thus obtained (yields 92.3%).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[Cl:21][C:22]1[N:23]=[C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[S:25][CH:26]=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30][N:1]2[CH:2]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])[S:25][CH:26]=1
Reactant: O=Cc1cccc(-c2nc(Cl)cs2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(-c2nc(Cl)cs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with 3-(4-chlorothiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 444.95 g/mol.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=1[O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br-].[Mg+2].[Br-].[Mg].BrCCBr.[CH:39]([C@@H:42]1[CH2:46][C@@H:45]([C@@H:47]([N:55]=[N+:56]=[N-:57])[CH2:48][C@@H:49]([CH:52]([CH3:54])[CH3:53])[CH:50]=[O:51])[O:44][C:43]1=[O:58])([CH3:41])[CH3:40].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH:39]([C@@H:42]1[CH2:46][C@@H:45]([C@@H:47]([N:55]=[N+:56]=[N-:57])[CH2:48][C@@H:49]([CH:52]([CH3:53])[CH3:54])[CH:50]([OH:51])[C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:19]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:20]=2)[O:44][C:43]1=[O:58])([CH3:40])[CH3:41]
Reactant: COCCCOc1cc(Br)ccc1OCCCOCc1ccccc1
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](C[C@H](C=O)C(C)C)N=[N+]=[N-])OC1=O
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: BrCCBr
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCCOc1cc(C(O)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCOCc1ccccc1
Temperature: -75 °C
Reaction time: 0.33 h

Procedure:
1.3 ml of a 0.9M solution of butyllithium in hexane are slowly added dropwise to a solution, stirred at -75° C., of 500 mg of 4-(3-benzyloxypropyloxy)-3-(3-methoxypropyloxy)-bromobenzene in 2 ml of tetrahydrofuran. The reaction mixture is stirred for 20 minutes at -75° C., and then a suspension of magnesium bromide, freshly prepared from 44.5 mg of magnesium powder and 0.158 ml of 1,2-dibromoethane in 3 ml of tetrahydrofuran at room temperature, is added dropwise. The reaction mixture is stirred for a further 30 minutes at -75° C., and then a solution of 172 mg of 3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxo-butyl]-tetrahydrofuran-2-one in 2 ml of tetrahydrofuran is added dropwise. The mixture is again stirred for 30 minutes at -75° C., and then 1.2 ml of saturated ammonium chloride solution are added dropwise at the same temperature. The reaction mixture is brought to room temperature and is then extracted three times with ethyl acetate. The organic phases are washed with water (2×) and saturated sodium chloride solution (1×), dried over magnesium sulfate, combined and concentrated by evaporation, and the residue is purified by means of FC (2×30 g of silica gel, hexane/ethyl acetate=6:2), yielding the title compound: Rt (hexane/ethyl acetate=2:1)=0.23; HPLC Rt =20.27 and 21.07 minutes (diastereoisomeric mixture); FAB-MS M+ =611.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]2=[O:21])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[CH:10]=2)[CH2:6][O:7]1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (56.5 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.5 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring at room temperature for 3 h, the mixture was filtered and rinsed with isopropanol and hexanes/EtOAc (7:3) to give the title compound (46.9 mg, 73%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([OH:5])=O.[CH2:27]([NH2:29])[CH3:28]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([NH:29][CH2:27][CH3:28])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CCN
Product: CCNC(=O)C(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O

Procedure:
Starting materials: 2,6,10,14-tetramethyl-18-oxo-2,6,10,14-nonadecatetraenoic acid and a 70% aqueous ethylamine solution