Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:29](=[O:31])[CH3:30]>O1CCCC1>[CH2:13]([O:20][C:21]([C:23]1([CH:29]([OH:31])[CH3:30])[CH2:28][CH2:27][CH2:26][O:25][CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(OCc1ccccc1)C1CCCOC1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)C1(C(=O)OCc2ccccc2)CCCOC1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 40.2 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (4.7 mL, 33.316 mmol, dried over calcium hydride) in anhydrous tetrahydrofuran (60 mL) was treated with a solution of n-butyllithium in hexanes (12.5 mL, 31.234 mmol, 2.5 M). After stirring at −78° C. for 25 minutes, the mixture was treated with a solution of tetrahydro-pyran-3-carboxylic acid benzyl ester (4.587 g, 20.823 mmol) in anhydrous tetrahydrofuran (20 mL). After stirring at −78° C. for 15 minutes, the mixture was treated with acetaldehyde (3.5 mL, 62.469 mmol). After stirring at room temperature for 45 minutes, the reaction was quenched at 0° C. with hydrochloric acid (2 M, 50 mL). The aqueous layer was saturated with sodium chloride, extracted with dichloromethane (2 x). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 3:2 to afford the title compound (2.212 g, 40%) as a yellow oil and as a 3:1 mixture of diastereoisomers. LCMS (m/z) 287.0 [M+Na], Tr=2.00 min.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11]>COCCOCCOC>[CH2:10]([OH:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:13]
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Solvent: COCCOCCOC
Product: OCCCCCCCCCCO

Procedure:
In step 2 a di-aldehyde molecule is formed in solution by reacting sebacic acid with thionyl chloride or sulfur oxychloride (SOCl2) to form Sebacoyl chloride. The resultant Sebacoyl chloride is reacted with LiAl[t-OButyl]3H and diglyme to yield 1,10-decanediol as shown below:
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:11])[CH2:9][CH3:10]>C1(C)C=CC=CC=1>[CH2:8]([NH:11][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH2:9][CH3:10]
Reactant: COCC(Cl)C=O
Reactant: CCCN
Solvent: Cc1ccccc1
Product: CCCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Propylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-propylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([NH:17][C@@H:18]2[C:34](=[O:35])[N:20]3[C:21]([C:31]([OH:33])=[S:32])=[C:22]([C:25]4[S:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl>[NH2:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([NH:17][C@@H:18]2[C:34](=[O:35])[N:20]3[C:21]([C:31]([OH:33])=[S:32])=[C:22]([C:25]4[S:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: Cc1nnc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4nsc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)s1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4nsc(N)n4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution of 7β-[2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (800 mg) in dichloromethane (2.4 ml) was added trifluoroacetic acid (10.4 ml). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into diisopropyl ether (150 ml). The precipitate was collected by filtration and dried. The precipitate was dissolved in a mixture of aqueous sodium hydrogen carbonate (212 mg/30 ml) and tetrahydrofuran (10 ml). The solution was washed with ethyl acetate (30 ml). To the aqueous layer was added a mixture of tetrahydrofuran (15 ml) and ethyl acetate (45 ml), adjusted to pH 2 with 1N-hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (490 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:17][N:16]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:26])[CH:14]([N:27]2C(=O)C3=CC=CC=C3C2=O)[CH2:13][S:12]1.CNN>>[NH2:27][CH:14]1[CH2:13][S:12][CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:17][N:16]([CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C:15]1=[O:26]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccc3ccccc3c2)SCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CNN
Product: CC(C)(C)OC(=O)CN1CC(c2ccc3ccccc3c2)SCC(N)C1=O
Yield: 106.9 %

Procedure:
3.25 g of t-butyl α-[2-(2-naphthyl)-5-oxo-6-phthalimidoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] were subjected to dephthaloylization with methylhydrazine in the same manner as described in Example 36(g), to give 2.6 g of the title compound as an amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]>O1CCCC1.[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(F)cc(C=CC(=O)O)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(F)cc(CCC(=O)O)cc1F

Procedure:
A solution of 3-(3,5-difluoro-4-methoxyphenyl)propenoic acid (0.078 mol) in tetrahydrofuran (100 ml) and a slurry of 10% palladium on carbon (2 g) in ethyl acetate were reacted substantially as described in Example 7C above to obtain 16.7 g (99%), white crystals: mp 72°-73°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[C:14]([F:21])[CH:13]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:25][CH:22]2[CH2:24][CH2:23]2)=[O:17])=[C:14]([F:21])[CH:13]=1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(-c2ncnc3ccc(Cl)cc23)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1ccc(-c2ncnc3ccc(Cl)cc23)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
0.2 g 4-(6-chloroquinazolin-4-yl)-2-fluorobenzoic acid (compound in Production Example 386), 41 mg cyclopropylamine and 0.12 mL triethylamine were dissolved in 6 mL dichloromethane, then 320 mg benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction solution was purified by NH silica gel column chromatography (hexane/ethyl acetate) and then recrystallized from methanol/ethyl acetate/ether, to give 162 mg of the title compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[CH3:10][S-:11].[Na+].C1COCC1.C(OCC)(=O)C>O>[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([S:11][CH3:10])[N:3]=1)#[N:9]
Reactant: N#Cc1cncc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CSc1cncc(C#N)n1
Yield: 82.7 %

Procedure:
A mixture of 2-chloro-6-cyanopyrazine (1.40 g, 10.0 mmol), sodium thiomethoxide (0.78 g, 11.0 mmol) and THF (100 ml) was refluxed for 2 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated to give the titled compound (1.25 g, 83%) as pale yellow crystals.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28](Cl)[N:27]=[C:26]([Cl:32])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[CH2:38][N:39]1[C:43]2[N:44]=[CH:45][N:46]=[CH:47][C:42]=2[N:41]=[N:40]1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:32][C:26]1[N:25]=[C:24]([NH:23][NH:22][C:20](=[O:21])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:8][N:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[O:11])[C:29]([F:30])=[C:28]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][N:39]2[C:43]3[N:44]=[CH:45][N:46]=[CH:47][C:42]=3[N:41]=[N:40]2)[N:27]=1
Reactant: c1ncc2nnn(C[C@@H]3CCCN3)c2n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(Cl)c1F)OCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(N2CCC[C@H]2Cn2nnc3cncnc32)c1F)OCc1ccccc1
Temperature: 65 °C
Yield: 23.7 %

Procedure:
{(2R)-2-(Cyclopentylmethyl)-3-[2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl}[(phenylmethyl)oxy]formamide (136 mg, 0.278 mmol) and 3-[(2S)-2-pyrrolidinylmethyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine (63 mg, 0.308 mmol) were dissolved in DMSO (5 mL), then DIEA (59 μL, 0.308 mmol) was added, and the solution was heated at 65° C. overnight. When the reaction was complete as determined by LCMS, the solution was concentrated in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(2S)-2-(3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-1-pyrrolidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (43 mg, 21%). LCMS: (M+H)+: 651.6.
Reaction SMILES: [CH3:1][C:2]1C=C[C:5]2C=1C(C)=[C:8](C)[C:7]1=[C:13]([CH3:17])[C:14]([CH3:16])=[C-:15][C:6]=21.[Li+].[CH2:19]=[CH2:20].C=C.C=C.C=C.[Cl-].[Cl-].[Rh:29].[Rh]>C1COCC1.CCCCCC>[CH2:1]=[CH2:2].[CH2:19]=[CH2:20].[Rh:29].[CH3:19][CH:15]1[C:14]([CH3:16])=[C:13]([CH3:17])[C:7]([CH3:8])=[C:6]1[CH3:5]
Reactant: CC1=[C-]c2c3c(c(C)c(C)c2=C1C)=C(C)C=C3
Agent: [Rh]
Agent: C=C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=C(C)C(C)C(C)=C1C
Temperature: 25 °C
Yield: 261.4 %

Procedure:
All operations are performed under an inert atmosphere and with dry, degassed solvents. Lithium pentamethylcyclopentaindenide powder (720 mg, 5.06 mmoles) is added in several portions to a cooled slurry of 1.0 g (2.54 mmoles) of chlorobis(ethylene)rhodium(I) dimer in 40 ml of THF. The mixture darkens as it comes to room temperature. The mixture is stirred several hours at room temperature then the solvent is stripped off at reduced pressure. The black residue is taken up in hexane, filtered and passed through a 6-inch column of activated neutral alumina with hexane eluent. The yellow fraction is collected which yields 980 mg of pentamethylcyclopentadiene rhodium bisethylene as a yellow solid (64 percent yield).
Reaction SMILES: [ClH:1].[C:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][CH2:6]1)(O)=[O:3].S(Cl)([Cl:32])=O>CCOCC>[ClH:32].[Cl:1][C:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][CH2:6]1)=[O:3]
Reactant: O=C(O)C1CCN(CCCCOc2ccccc2CCc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCOCC
Product: O=C(Cl)C1CCN(CCCCOc2ccccc2CCc2ccccc2)CC1

Procedure:
To 6.0 g of 2-[4-(4-carboxypiperidino)butoxy]bibenzyl hydrochloride was added dropwise 15 ml of thionyl chloride with stirring. The reaction mixture was stirred at room temperature for 3 hours. As the reaction proceeded the reaction mixture became homogenous. Upon completion of the reaction, anhydrous ether was added and the resultant oily product was washed well twice or three times with anhydrous ether. To the washed oil was added anhydrous ether and the mixture was allowed to stand yielding crystalline 2-[4-(4-chlorocarbonylpiperidino)butoxy]bibenzyl hydrochloride which was sufficiently dried for use in the subsequent reaction. To a solution of 10 ml of 50% aqueous dimethylamine solution and 10 ml of tetrahydrofuran cooled in an ice-salt bath was quickly added 1.5 g of crystalline 2-[4-(4-chlorocarbonylpiperidino)butoxy]bibenzyl hydrochloride with stirring. The mixture was allowed to react for 1.5 hours and then concentrated. To the concentrate was added 2N-NaOH aqueous solution and the product was extracted with ether. The extract from ether was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. To the ether solution was added 20% ethanolic hydrogen chloride to yield a precipitate. Recrystallization from etherethanol gave 1.2 g (78% yield) of 2-[4-(4-dimethylcarbamoylpiperidino)butoxy]bibenzyl hydrochloride, m. p. 139°-160° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][C:18]1N(C)[C:21]2C=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1>CN(C)C=O>[CH3:21][C:20]1[N:19]=[C:18]([CH2:17][N:7]([C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(Nc2ccccn2)nc1
Reactant: Cn1c(CCl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(CN(c2ccccn2)c2ccccn2)n1

Procedure:
To a flask were added 1.1 g of 2,2′-dipyridylamine and 25 ml of N,N-dimethylformamide. To this mixture were added 0.32 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 10 C for ten minutes, 1.2 g of 2-(chloromethyl)-1-methyl-1H-benzimidazole in 5 ml of N,N-dimethylformamide were added. The reaction mixture was stirred at 22 C for several hours, and then quenched with 40 ml water. The product was extracted with 50 ml ethyl acetate, and then extracted with 30 ml of 1M hydrochloric acid, and basified with 3M sodium hydroxide. Following extraction with 20 ml ethyl acetate, the product was purified by silica gel chromatography using 33% ethyl acetate, 62% hexane, and 5% methanol, resulting in an oil which crystallized on standing. After drying, 0.6 g of a yellow solid remained.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].C(C1C(S(C)(=O)=O)=C(Br)C=CC=1C(OC)=O)C.C1(B(O)O)C=CC=CC=1.[Cl-].C[N+]1C=CC=CC=1Cl.[Cl-].[NH2:58][C:59]([NH2:61])=[NH2+:60].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[NH2:60][C:59]([NH2:61])=[N:58][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c(C(=O)O)ccc(-c2ccccc2)c1S(C)(=O)=O
Reactant: NC(N)=[NH2+]
Agent: CCc1c(C(=O)OC)ccc(Br)c1S(C)(=O)=O
Agent: C[n+]1ccccc1Cl
Agent: OB(O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCc1c(C(=O)N=C(N)N)ccc(-c2ccccc2)c1S(C)(=O)=O
Reaction time: 0.25 h

Procedure:
1.0 g of 2-ethyl-3-methylsulphonyl-4-phenylbenzoic acid [obtainable by reacting methyl 2-ethyl-3-methylsulphonyl-4-bromobenzoate with phenylboronic acid in the presence of tetrakis(triphenylphosphine)-Pd(0) and then hydrolyzing] is dissolved in 15 ml of 1-methylpyrrolidone, and 0.67 g of 1-methyl-2-chloropyridinium chloride is added to this solution which is then stirred for 15 min. 0.9 g of guanidinium chloride and 2.6 ml of diisopropylethylamine are then added, and the mixture is stirred at room temperature for one hour. N-Diaminomethylene-2-ethyl-3-methylsulphonyl-4-phenylbenzamide is obtained after customary working-up.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=O)[CH3:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([C:2]([CH3:6])=[C:3]([CH3:4])[N:7]=2)[CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)C(C)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1nc2ccc(Br)cn2c1C
Yield: 16.9 %

Procedure:
13.53 mL (130.06 mmol) of 3-bromobutan-2-one are added to a mixture, stirred at 20° C., of 5 g (28.90 mmol) of 2-amino-5-bromopyridine and 4.85 g (57.80 mmol) of sodium hydrogen carbonate in 100 mL of ethanol. The mixture is refluxed for 12 hours and then concentrated under reduced pressure. The mixture obtained is taken up in 100 mL of water. The pH of the solution is basified by successive additions of potassium carbonate. The mixture is then extracted with 3×50 mL of ethyl acetate. The combined organic phases are washed with water (50 mL), dried over sodium sulfate and then concentrated under reduced pressure. An oil is obtained, which is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 1.1 g of the expected product are thus isolated.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: C1CCNC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1I
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1I

Procedure:
A solution of N-(3-iodo-4-methylphenyl)-2-chloro-isonicotinamide (Intermediate 20) (7.00 g, 18.8 mmol) in pyrrolidine (20 ml) was heated at 80° C. under an atmosphere of nitrogen for 16 hours. Excess pyrrolidine was removed in vacuo and the residue was titurated with dietheyl ether (20 ml). The resulting solid was collected by filtration and dried in vacuo to give N-(3-iodo-4-methylphenyl)-2-pyrrolidin-1-yl-isonicotinamide as a pale yellow solid (7.73 g, 18 mmol). LCMS: retention time 2.77 min MH+408. NMR: δH [2H6]-DMSO 10.29 (1H, s), 8.29 (1H, d), 8.20 (1H, d), 7.71 (1H, dd), 7.72 (1H, dd), 6.97 (1H, brd), 6.88 (1H, b), 3.45 (2H, apparent t), 3.09 (2H, m), 2.35 (3H, s), 1.98 (2H, m), 1.82 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7](OC)[CH:6]=[CH:5]2.[CH3:17][NH2:18]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([NH:18][CH3:17])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6-bromo-2 methoxy-1-nitronaphthalene (5.64 g, 20 mmol) in 100 ml of dry N,N-dimethylformamide saturated with methylamine was stirred in a stoppered flask at 80° C. for 4 h. During the reaction period the mixture was saturated twice with a further quantity of methylamine. The cooled mixture was poured into 1 l of ice/water. After stirring for 1 h, the orange solid was collected by filtration and washed with water, and dried in vacuo over phosphorus pentoxide affording 5.43 g (96%) of the title compound. M.p. 169°-170° C.; 1H-NMR (CDCl3): 3.11 (d, J=5 Hz, 3H, CH3), 7.00 (d, J=9 Hz, 1H, ArH), 7.45- 7.78 (m, 3H, ArH), 8.60 (d, J =9 Hz, 1H, ArH), 8.7 (broad, 1H, NH).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:50])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][N:28]2[CH2:32][CH2:31][CH2:30][CH:29]2[CH2:33][O:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=2[N+:45]([O-])=O)=[O:26])=[CH:20][C:19]=1[O:48][CH3:49])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:45][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:35]=1[O:34][CH2:33][CH:29]1[CH2:30][CH2:31][CH2:32][N:28]1[NH:27][C:25](=[O:26])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:16]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[O:50])=[C:19]([O:48][CH3:49])[CH:20]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)c1ccc(OCC2CCCN2NC(=O)Cc2ccc(NC(=O)Nc3ccccc3OCc3ccccc3)c(OC)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(OCC2CCCN2NC(=O)Cc2ccc(NC(=O)Nc3ccccc3O)c(OC)c2)c(N)c1
Reaction time: 17 h
Yield: 87.5 %

Procedure:
A solution of methyl 4-[1-[4-[N′-(2-benzyloxyphenyl)ureido]-3-methoxyphenylacetamido]-2-pyrrolidinylmethoxy]-3-nitrobenzoate (1.52 g, 2.27 mmol) in MeOH (20 mL) and THF (5 mL) was hydrogenated over 5% Pd—C (wet, 52.2%; 1.21 g) under hydrogen atmosphere (4 kg/cm2) at room temperature After being stirred for 17 hr, the catalyst was filtered off and the filtrate was concentrated to dryness. Chromatography of the residue with EtOAc as eluent gave methyl 3-amino-4-[1-[4-[N′-(2-hydroxyphenyl)ureido]-3-methoxyphenylacetamido]-2-pyrrolidinylmethoxy]benzoate (1.12 g, 90%) as a brownish amorphous solid. 1H-NMR (CDCl3) δ 1.97–2.10 (m, 4H), 3.44 (s, 3H), 3.52–3.63 (m, 2H), 3.85 (s, 3H), 4.10–4.18 (m, 2H), 4.53 (m, 1H), 6.65–6.67 (m, 4H), 6.93–7.02 (m, 3H), 7.33 (d, J=2.2 Hz, 1H), 7.36 (dd, J=8.3, 2.2 Hz, 1H), 7.60 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 9.47 (broad s, 1H); FAB-MS m/z 549 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[CH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]#[C:14][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C#Cc1c(-c2ccc(Cl)cc2)noc1C
Reactant: Brc1ccccn1
Product: Cc1onc(-c2ccc(Cl)cc2)c1C#Cc1ccccn1
Yield: 87 %

Procedure:
As described for example 11c, 3-(4-chloro-phenyl)-4-ethynyl-5-methyl-isoxazole (109 mg, 0.50 mmol) instead of 4-ethynyl-5-methyl-3-phenyl-isoxazole was converted (using 2-bromopyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 129 mg, 87%) which was obtained as a light brown solid. MS: m/e=295.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].ClC1C=CC=CC=1Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(OCC)(=O)C>[CH3:21][CH:20]([CH3:22])[C:19]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][C:3]([O:2][CH3:1])=[O:18])=[CH:7][CH:8]=1)=[O:23]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1Cl
Product: COC(=O)CC(c1ccccc1)c1ccc(C(=O)C(C)C)cc1
Temperature: 4 °C
Reaction time: 7 h
Yield: 66.8 %

Procedure:
A mixture of 80 g (0.333 mol) of methyl3,3-diphenylpropanoate, 42.6 g (0.399 mol) of isobutyryl chloride, and 600 mol of 1,2-dichlorobenzene is cooled to 4° C. Aluminum chloride (112 g, 0.832 mol) is added portion wise over 2 hours while the reaction temperature is kept between −5 and 5° C. The reaction is kept within this temperature range for 7 hours, and then stirred at room temperature for 13 hours. The reaction mixture is poured into a mixture of ice and concentrated hydrochloric acid, and then stirred for 1 hour. The organic layer is washed twice with dilute hydrochloric acid, and then concentrated under vacuum to give 115 grams of crude product. Purification by column chromatography on silica gel with 9:1 heptane:ethyl acetate as the eluent gives 69 g (60% yield) of methyl 3-[4-(2-methylpropionyl)phenyl]-3-phenylpropanoate.