Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[N:4]([CH2:19][CH3:20])[S:5](=[O:18])(=[O:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[N:22]1([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:19]([N:4]1[C:3](=[O:21])[C:2]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:34][CH:33]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:5]1(=[O:18])=[O:17])[CH3:20]
Reactant: CCN1C(=O)C(Cl)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: CCN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-ethyl-5-[4-(trifluoromethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide and 4-morpholin-4-ylaniline in a similar manner as described for Example 11. 1H NMR (500 MHz, CDCl3): δ 1.51 (t, 3H), 2.98-3.01 (m, 4H), 3.81-3.83 (m, 4H), 3.88 (q, 2H), 6.52 (d, 2H), 6.64 (d, 2H), 7.22 (d, 2H), 7.36 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:45]([C:48]1[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=1)([O-:47])=[O:46].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([O:25][C:52](=[O:53])[C:51]2[CH:50]=[CH:49][C:48]([N+:45]([O-:47])=[O:46])=[CH:56][CH:55]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 4 h

Procedure:
To a stirred mixture of (±)-trans-4-benzyloxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1 mmol, 0.35 g), triphenylphosphine (1.5 mmol, 0.393 g) and p-nitrobenzoic acid (1.5 mmol, 0.25 g) in anhydrous THF (6 mL) at −60° C. was added DIAD drop-wise over 5 min period. After completion of addition, the reaction mixture was stirred for 4 h during which period the reaction mixture was slowly let attain room temperature. The reaction mixture was diluted with ether (100 mL) and washed with saturated sodium bicarbonate solution (2×50 mL). The organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with 30% ethyl acetate in hexanes to get (±)-cis-4-benzyloxycarbonylamino-3-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH3:59])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:56]([O:55][CH2:54][CH2:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:51][CH:50]=1)[CH2:57][CH2:58][CH3:59]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 4-(2-butoxyethoxy)phenyl borate (221 mg) and potassium carbonate (234 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36 mg), and the mixture was refluxed for 8 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 98) (330 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:37]=[CH:36][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)=[O:12])=[CH:9][CH:8]=1.[OH-].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:12])=[CH:36][CH:37]=1
Reactant: COC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1cccnc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2cccnc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 88 %

Procedure:
In a similar manner to that described in Example 2, methyl 3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]-2-(pyridine-3-yloxy)propionate (248 mg), which is the product of Example 154, was reacted with aqueous sodium hydroxide solution (1N, 1.00 ml) and the reaction mixture was treated to give the title compound (212 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,5-dichloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I(Cl)(=O)=O.[I:5](Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[NH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH3:28])[CH:22]=1.C(=O)([O-])[O-].[Ca+2]>ClCCl.CO>[NH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH3:28])[C:22]=1[I:5]
Reactant: Cc1cc(N)cc(C)n1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N)c(I)c(C)n1
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Benzyltrimethylammonium dichloroiodate (6 g) was added to 4-amino-2,6-dimethylpyridine (2.1 g) and calcium carbonate (2.25 g) in dichloromethane/methanol (55 ml) (8:3 v/v) and the mixture was stirred for 16 hours. Solvent was removed by evaporation and the residue partitioned between 5% sodium metabisulphite solution and dichloromethane. The aqueous phase was separated and washed with dichloromethane. The aqueous phase was then basified with sodium carbonate and extracted with dichloromethane. The organic phase was washed with water, saturated sodium chloride solution and dried (MgSO4). Solvent was removed by evaporation and the residue purified by flash chromatography eluting with dichloromethane/methanol (9:1 v/v) to give 4-amino-2,6-dimethyl-3-iodopyridine (B) (1.7 g) as a light yellow solid, m.p. 103°-110° C.; NMR (CDCl3): 2.3(s,3H), 2.7(s,3H), 4.6(br s,2H), 6.3(s,1H); mass spectrum (chemical ionisation): 249 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:20][CH3:21])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N+:17]([O-])=O)=[CH:5][CH2:4]1)[CH3:2].[Cl-].[NH4+]>C(O)C.[Fe]>[CH2:20]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[NH2:17])=[CH:5][CH2:4]1)[CH3:21]
Reactant: CCC1(CC)CC=C(c2ccc(OC)cc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCC1(CC)CC=C(c2ccc(OC)cc2N)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 120.8 %

Procedure:
To a solution of 1-(4,4-diethylcyclohex-1-enyl)-4-methoxy-2-nitrobenzene (2.4 g, 8.3 mmol) prepared in Example (6d) in ethanol (20 mL) were added an aqueous solution (5 mL) of ammonium chloride (2.2 g, 41 mmol) and iron powder (1.2 g, 20.7 mmol), and the mixture was stirred at an external temperature of 90° C. for 1 hour. The reaction mixture was passed through Celite for filtration, and then brine was added to the filtrate and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and then the filtrate was concentrated under reduced pressure to give 2.6 g of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)[N:8]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)CC1

Procedure:
3 g of 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-(4-fluoro-phenyl)-quinoline-3-carboxylic acid are refluxed in 30 ml of pyridine with 2.7 g of N-methylpiperazine for 6 hours. The solvent is distilled off in vacuo, the residue is taken up in 30 ml of water and the precipitate is filtered off cold with suction, washed with water, dried in vacuo over calcium chloride at 100° C. and recrystallized from glycol monomethyl ether.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[C:12](=[O:19])[O:11][C:10]=2[CH:20]=1.[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[CH3:22].C(N(CC)CC)C>O1CCCC1>[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=4[C:12](=[O:19])[O:11][C:10]=3[CH:20]=2)[CH2:27][CH2:26]1)(=[O:23])[CH3:22]
Reactant: O=c1oc2cc(OCCCBr)ccc2c2c1CCCC2
Reactant: CC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCCC4)CC1

Procedure:
A mixture of 17.3 g. (0.051 mole) 3-(3-bromopropoxy)-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one, 7.3 g. (0.051 mole) 4-acetamidopiperidine, 5.2 g. triethylamine and 100 ml. tetrahydrofuran is heated under reflux for 14 hours and then cooled and filtered. The precipitate obtained is washed with tetrahydrofuran and water and dried in a vacuum. There are obtained 11.3 g. (55% of theory) of the desired compound (m.p. 167°-168° C.) which is identical to the compound of Example 23.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH3:2].[CH:33](O)(C)C.Cl.O1CCOCC1>>[CH:1]([O:3][C:4](=[O:32])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])([CH3:33])[CH3:2]
Reactant: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Reactant: CC(C)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.7 %

Procedure:
(R)-3-[N-(3′-Chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-propionic acid ethyl ester (1.4 g, 3.0 mmol) was dissolved in isopropyl alcohol (20 mL, 0.2 mol) and 4 M HCl in dioxane (9 mL, 40 mmol) was added. The mixture was stirred at room temperature overnight (18 hours). The mixture was warmed to 60° C. for 1 hour, then cooled back to room temperature and stirred for 2 hours. The mixture was concentrated and purified (Interchim C18 reverse phase chromatography column, 30-90% MeCN in water for 22 minutes). The clean fractions were combined and lyophilized to yield the title compound (110 mg; purity 98%). MS m/z [M+H]+ calc'd for C23H24ClN3O6, 474.14. found 474.2.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+].[BH4-].[Na+]>CO>[CH2:6]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](N)CO
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](CO)NCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of (2R)-2-amino propanol (1.2 equivalents), benzaldehyde (1 equivalent), NaHCO3 (1.5 equivalents), and MeOH, (˜1 M) was heated at reflux for 4 hours and then cooled to 0° C. Sodium borohydride (4.8 equivalents) was added portionwise to the stirred reaction mixture during a period of 2 hours at ca. 10° C. The whole was stirred at room temperature for 4 hours. The insoluble materials were filtered off and then the filtrate was concentrated to dryness. The residue was dissolved in CH2Cl2, and the solution was washed successively with water (2×) and brine (1×). The organic extracts were collected and dried (Na2SO4). The solvent was evaporated to give the desired product as a colorless oil, which solidified on standing and was used in the next step without further purification. GC/MS: 134 (100%, M+−CH2OH), Rt 11.57 minutes.
Reaction SMILES: C1(C#C)C=CC=CC=1.[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]#[CH:11].[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:11]=[C:10]([CH2:9][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#CCOc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(COc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with phenyl propargyl ether to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 36% yield: mp 140-143° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 7.38-7.26 (m, 7H), 7.02-6.98 (m, 3H), 6.15 (t, J=6.0 Hz, 1H), 5.28 (s, 2H), 4.63 (d, J=6.0 Hz, 2H), 2.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.8, 157.9, 155.3, 153.2, 145.6, 137.4, 129.6, 128.9, 127.9, 127.9, 124.7, 121.5, 120.3, 114.7, 61.5, 44.4, 17.4; MS (ES+) m/z 406.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:12]3[F:19])[C:6]=2[N:7]=1.Cl.[OH-:22].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:12]3[F:19])[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Nc1nc2c(ccn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1

Procedure:
A mixture of the compound from Step I (4 mg, 0.08 mmol) in 2N aqueous NaOH (1.2 mL) was stirred at reflux temperature for 1.5 h. The solution was cooled in an ice-bath, neutralized with 2 N aqueous HCl and evaporated to dryness. The residue was suspended in MeOH, mixed with silica gel and evaporated. The solid residue was placed onto a silica gel column (packed in a solvent system of CH2Cl2/MeOH: 10/1) which was eluted with a solvent system of CH2Cl2/MeOH: 10/1. The fractions containing the product were collected and evaporated to dryness to yield the title compound (20 mg) as a white solid.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][N:5]=1>O1CCOCC1>[Br:1][CH:10]([C:8]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:3])[CH:9]=1)[C:11](=[O:13])[CH3:12]
Reactant: BrBr
Reactant: CC(=O)Cc1ccnc(Cl)c1
Solvent: C1COCCO1
Product: CC(=O)C(Br)c1ccnc(Cl)c1

Procedure:
Bromine (1.36 ml, 26 mmol) is added dropwise to a stirred solution of 1-(2-chloro-pyridin-4-yl)-propan-2-one (Example 2a, 5.0 g, 29.5 mmol) in dioxane (150 ml) over 45 minutes at 5-10° C. After 20 minutes at room temperature the solvent is removed in vacuo to afford the titled compound as a yellow solid.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([CH:24]=[CH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:27]=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:16]=2)[C:11]([CH3:37])([CH3:36])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][O:34][C:32](=[O:33])[C:29]1[CH:28]=[CH:27][C:26]([CH:25]=[CH:24][CH:18]([C:15]2[CH:16]=[C:17]3[C:12]([C:11]([CH3:37])([CH3:36])[CH2:10][CH2:9][NH:8]3)=[CH:13][CH:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:31][CH:30]=1
Reactant: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)NCCC2(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
A solution of 7-{1-[2-(4-methoxycarbonyl-phenyl)-vinyl]-hexyl}-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.98 g) in 10 mL of dichloromethane was treated with 1.5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for four hours and then was concentrated in vacuo to yield 0.72 g of 4-[3-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[C:20]([CH3:22])[CH:21]=1)=[O:4].[OH-].[Li+]>>[CH2:23]([N:18]1[C:17]([N:6]2[CH2:7][C@H:8]([S:10]([CH2:13][CH:14]3[CH2:16][CH2:15]3)(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[CH:21][C:20]([CH3:22])=[N:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)CC3CC3)C[C@H]2C(=O)O)n(Cc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-4-cyclopropylmethanesulfonyl-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=404.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CS([C:12]1[N:17]=[C:16]([Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:15]=[CH:14][N:13]=1)(=O)=O.O1CCOCC1>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:12]2[N:17]=[C:16]([Sn:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:15]=[CH:14][N:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(S(C)(=O)=O)n1
Solvent: C1COCCO1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccnc(N2CCN(C)CC2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
1-Methylpiperazine (0.160 mL, 1.44 mmol) was added to a solution of 2-(methylsulfonyl)-4-(tributylstannyl)pyrimidine (0.250 g, 0.481 mmol, synthesized as described in Majeed, A. J., et al. Tetrahedron 1989, 45, 993-1006) and 1,4-dioxane (1.0 mL) under nitrogen. After about 2 h, the solution was warmed to about 50° C. After about 30 min, the solution was warmed to about 80° C. After about 30 min, a reflux condenser was attached and the solution was warmed to about 100° C. After about 16 h, the brown solution was allowed to cool to ambient temperature. Water (5 mL) was added. The mixture was extracted with EtOAc (2×5 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 2-10% MeOH/DCM to afford 2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine (0.127 g, 56%): 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=4.6 Hz, 1H), 6.63 (d, J=4.6 Hz, 1H), 3.98-3.82 (m, 4H), 2.63-2.48 (m, 4H), 2.40 (s, 3H), 1.70-1.43 (m, 6H), 1.42-1.20 (m, 6H), 1.18-0.97 (m, 6H), 0.88 (t, J=7.3 Hz, 9H).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[N:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[CH:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1.C1CCN2C(=NCCC2)CC1.CCCCCC.C(OCC)(=O)C>C1COCC1>[F:10][C:6]1[CH:5]=[C:4]([C:3]#[C:2][C:12]2[CH:17]=[N:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cncc(C(Br)C(Br)c2cccc(F)c2)n1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCC
Product: Cc1cncc(C#Cc2cccc(F)c2)n1
Yield: 25.3 %

Procedure:
2-[1,2-Dibromo-2-(3-fluorophenyl)ethyl]-6-methylpyrazine (2.97 g, 7.94 mmol) was dissolved in THF (40 mL), treated with DBU (8.7 mL, 63 mmol), and heated to reflux. After 16 h the reaction mixture was cooled, filtered, concentrated in vacuo, and purified by column chromatography eluting with 80:20 then 75:25 hexane:ethyl acetate to afford 2-[(3-fluorophenyl)ethynyl]-6-methylpyrazine (427 mg, 25% yield). This material was carried on to the salt formation without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15]([CH2:17][CH:18](OC)OC)[CH3:16])=[O:14])=[CH:8][C:7]=1[S:23][CH2:24][CH3:25].Cl>O>[CH3:16][N:15]1[CH:17]=[CH:18][N:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:2]([Cl:1])[CH:3]=3)=[C:7]([S:23][CH2:24][CH3:25])[CH:8]=2)[C:13]1=[O:14]
Reactant: CCSc1cc(NC(=O)N(C)CC(OC)OC)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Product: CCSc1cc(-n2ccn(C)c2=O)ccc1Oc1ccc(Cl)c(Cl)c1

Procedure:
N-[4-(3,4-Dichlorophenoxy)-3-(ethylthio)phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, theremometer and condenser. The mixture is refluxed for a period of about 30 minutes then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3-[4-(3,4-dichlorophenoxy)-3-(ethylthio)phenyl]-4-imidazolin-2-one.