Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:13][NH:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C23CCCC2CN(Cc2ccccc2)CC3)c1
Agent: [Pd]
Product: COc1cccc(C23CCCC2CNCC3)c1

Procedure:
4a-(3-Methoxyphenyl)-2-benzyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine was hydrogenated in the presence of palladium suspended on charcoal according to the procedure set forth in Example 21 to provide 4a-(3-methoxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine. B.P. 145°-160° C., 0.05 torr.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][CH:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][CH:24]([O:26][C:27](Cl)=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:32]([CH2:37][O:38][CH2:39][CH2:40][NH2:41])[O:33][CH2:34][CH2:35][NH2:36]>ClCCl>[CH3:1][C@@H:2]([C@@H:9]1[C@:13]2([CH3:31])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][CH2:14]2)[C@:21]2([CH3:30])[C:20]([CH2:25][C@@H:24]([O:26][C:27](=[O:28])[NH:36][CH2:35][CH2:34][O:33][CH2:32][CH2:37][O:38][CH2:39][CH2:40][NH2:41])[CH2:23][CH2:22]2)=[CH:19][CH2:18]3)[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: NCCOCCOCCN
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCOCCOCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of cholesteryl chloroformate (1 g, 2.23 mmol) in 25 mL dichloromethane was added dropwise under stirring to a solution of 2,2′-(ethylenedioxy)bis-(ethylamine) (495 mg, 3.34 mmol) in 75 mL dichloromethane. The reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane and extracted with water. The organic extract was dried over anhydrous MgSO4 dihydrate, filtered and evaporated. After purification on amino-modified silica gel (eluent: MeCl2->MeCl2/MeOH=975:25 v/v) the product (615 mg) was obtained as a white, waxy solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)C>[NH:10]([C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: Fc1cc(I)ccn1
Solvent: CCO
Solvent: O
Product: NNc1cc(I)ccn1
Temperature: 24.5 °C
Reaction time: 20 h

Procedure:
A solution of 2-fluoro-4-iodopyridine (prepared as described in Rocca, P. et al J. Org. Chem. 1993, 58, 7832-7838) (8.72 g, 39.1 mmol) in 80 mL of ethanol was treated with 20 mL of hydrazine hydrate and the mixture was stirred at room temperature (24-25° C.) for 20 hours. At the end of the reaction, the mixture was concentrated in vacuum and the resulting solid triturated with a mixture of hexanes/diethyl ether affording (8.52 g, 93%) the desired compound that was used in the following steps without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([C:13]3[CH:14]=[C:15]([C:19]#[C:20][CH:21]([NH:23][OH:24])[CH3:22])[CH:16]=[CH:17][CH:18]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[Si]([N:29]=[C:30]=[O:31])(C)(C)C.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([C:13]3[CH:14]=[C:15]([C:19]#[C:20][CH:21]([N:23]([OH:24])[C:30]([NH2:29])=[O:31])[CH3:22])[CH:16]=[CH:17][CH:18]=3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C#Cc1cccc(C2CC(c3ccc(F)cc3)=NO2)c1)NO
Solvent: C1CCOC1
Solvent: CO
Product: CC(C#Cc1cccc(C2CC(c3ccc(F)cc3)=NO2)c1)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of the product of Step 2, above (11, 1.9 g, 5.8 mmol), in THF (10 ml) was added TMS-NCO (1.1 ml, 8.8 mmol), and the reaction mixture was stirred at room temperature for 2 hours. To the mixture was added methanol (5 ml) and the reaction mixture was stirred for 10 minutes and then solvent was removed by evaporation. The residue was chromatographed on silica gel (5% methanol/ethyl acetate) to give the crude title compound. Recrystallization from methanol/n-hexane/ethyl acetate afforded the title compound (12, 1.5 g, 67% yield) as colorless solids.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.[CH:29]1([CH2:32][NH2:33])[CH2:31][CH2:30]1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[C:7]([NH:33][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1
Reactant: NCC1CC1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Cl)c1ccc(OC)cc1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1NCC1CC1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(4-chloro-2-phenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (45 mg, 0.11 mmol) (from Example 12a supra) and cyclopropylmethylamine (1.0 mL) (Lancaster) was stirred at room temperature for 24 hours. The reaction mixture was then diluted with ethyl acetate (50 mL) and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude 3-(2-phenylamino-4-cyclopropylmethylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester which was used in the next step without further purification. (Yield 51.3 mg).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Essentially prepared according to Procedure G using 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.00 g, 4.10 mmol) and (S)-tert-butyl 2-methylpiperazine-1-carboxylate to give (S)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=412.3 (M+1).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH2:30]([CH:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)[CH2:31][CH3:32]>>[CH2:30]([CH:33]1[CH2:38][CH2:37][CH:36]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:35][CH2:34]1)[CH2:31][CH3:32]
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCCC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-n-propyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1I>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[F:20])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccccc1I
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1[N+](=O)[O-]
Yield: 106.5 %

Procedure:
Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F2) (525 mg, 2.0 mmol) and 2-fluoro-1-iodobenzene (0.35 mL, 3 mmol) according to the general procedure F. Obtained as a yellow solid (759 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[F:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: COc1ccc(OC)c(N)c1
Product: Oc1ccc2oc(-c3ccc(O)c(F)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 3-fluoro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 262–268° C.; MS m/e 244 (M−H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:14]([NH:15][C:16](=[O:25])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13](=[O:26])[N:8]2[C:9]=1[C:10]([O-:12])=[O:11].[Na+].[C:28]([O:34][CH2:35]Br)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:14]([NH:15][C:16](=[O:25])[CH2:17][O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13](=[O:26])[N:8]2[C:9]=1[C:10]([O:12][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:11]
Reactant: CC(C)(C)C(=O)OCBr
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
1 g of sodium 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate was disssolved in 50 ml of dimethyl sulphoxide, and 975 mg of pivaloyloxymethyl bromide were added thereto, after which the mixture was stirred at room temperature for 15 minutes. The mixture was then diluted with 200 ml of ethyl acetate, washed in turn with 50 ml of a saturated aqueous solution of sodium bicarbonate and 50 ml of a saturated aqueous solution of potassium bisulphate, and then dried over anhydrous magnesium sulphate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure and the resulting residue was chromatographed through 100 g of silica gel eluted with a 1:1 by volume mixture of hexane and ethyl acetate, to afford 750 mg of the desired pivaloyloxymethyl 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11]>N12CCN(CC1)CC2.C(Cl)(Cl)Cl>[OH:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:10](=[CH2:11])[C:9]([O:13][CH3:14])=[O:12]
Reactant: O=Cc1ccccn1
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: ClC(Cl)Cl
Product: C=C(C(=O)OC)C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
A 250-mL single-neck round-bottomed flask was charged with chloroform (100 mL), picolinaldehyde (10.7 g, 0.10 mol), methyl acrylate (8.60 g, 0.10 mol), and 1,4-diaza-bicyclo[2.2.2]octane (0.560 g, 5.00 mmol). The reaction mixture stirred at room temperature for 48 h. After this time the reaction was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 193a as dark yellow oil (11.6 g, 60%). MS-ESI: (M+H)+ 194.2. 1H NMR (500 MHz, CDCl3) δ 8.54 (d, J=5.0 Hz, 1H), 7.69-7.66 (m, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.22-7.20 (m, 1H), 6.36 (s, 1H), 5.97 (s, 1H), 5.62 (s, 1H), 4.85 (s, 1H), 3.74 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34]C)=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2cncnc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2cncnc2-c2nnn[nH]2)cc1

Procedure:
To a solution of methyl 2-butyl-1-[p-[4-(1H-tetrazol-5-yl)pyrimidin-5-yl]benzyl]benzimidazole-7-carboxylate (0.1 g, 0.2 mmol) in methanol (5 ml) was added 1N aqueous NaOH (0.5 ml) and the mixture was heated under reflux for 6 hours. After concentration to dryness, the residue was dissolved in water and the solution was neutralized with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and washed with water. Recrystallization from aqueous methanol afforded yellow powders (80 mg, 82%), m.p. 209°-212° C.
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:5]=1.Cl.N1CCC(C(C2C=CC3C(=CC=C(Cl)C=3)C=2)=O)CC1.Br[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)=[O:50].ClCCCC(C1C=CC(F)=CC=1)=O>>[F:22][C:3]([F:2])([F:21])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)=[O:50])[CH2:17][CH2:16]2)[CH:5]=1
Reactant: COc1ccc(C(=O)CCCCCBr)cc1
Reactant: FC(F)(F)c1cc(CC2CCNCC2)cc2ccccc12
Agent: Cl
Agent: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Product: COc1ccc(C(=O)CCCCCN2CCC(Cc3cc(C(F)(F)F)c4ccccc4c3)CC2)cc1

Procedure:
When in the procedure of Example 25, 4-[(4-trifluoromethyl-2-naphthyl)methyl]piperidine hydrochloride is substituted for 6-chloro-2-naphthyl 4-piperidyl ketone hydrochloride and 6-bromo-1-(4-methoxyphenyl)-1-hexanone substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, 6-[4-((4-trifluoromethyl-2-naphthyl)methyl)-1-piperidyl]-1-(4-methoxyphenyl)-1-hexanone is obtained.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([NH:16][CH2:20][C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:18]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(OC2CCN(C3CCC3)CC2)cc1)N1CCOCC1
Yield: 40.2 %

Procedure:
A mixture of 4-(1-Cyclobutyl piperidin-4-yloxy)aniline (0.5 g, 0.002 moles), 2-Chloro-1-(morpholin-4-yl)ethanone (0.5 g, 0.003) and potassium carbonate (0.56 g, 0.004 moles) in dimethylformamide (25 ml) was stirred at reflux temperature. After completion of reaction, the mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (250 mL) and water (250 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (chloroform: triethylamine, 9.5:0.5) to obtain the title compound 0.3 g (Yield: 40%).
Reaction SMILES: B(Br)(Br)Br.[NH:5]1[CH:9]=[C:8]([CH2:10][CH:11]2[C:19]3[C:14](=[CH:15][C:16]([CH:22]=[O:23])=[C:17]([O:20]C)[CH:18]=3)[CH2:13][CH2:12]2)[N:7]=[CH:6]1.O.[OH-].[NH4+]>C(Cl)Cl>[OH:20][C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][CH:11]2[CH2:10][C:8]2[N:7]=[CH:6][NH:5][CH:9]=2)=[CH:15][C:16]=1[CH:22]=[O:23]
Reactant: COc1cc2c(cc1C=O)CCC2Cc1c[nH]cn1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc2c(cc1O)C(Cc1c[nH]cn1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boron tribromide 1.0 M solution in methylene chloride (2 ml) is added dropwise to a stirred solution of 1-(1H-imidazol-4-ylmethyl)-6-methoxyindan-5-carbaldehyde (144 mg) in methylene chloride (10 ml) at −70° C. under a nitrogen atmosphere. After the addition the mixture is allowed to warm to room temperature and is stirred for 3 hours. The mixture is then poured into cold water and is made basic with ammonium hydroxide solution. The product is extracted into methylene chloride which is washed with water, dried with sodium sulfate and evaporated to dryness. The crude product is purified by flash chromatography using methylene chloride-methanol as eluent and crystallized from ethyl acetate.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[CH3:13][C:14]1[N:15]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[S:17][CH:18]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:19]([C:16]1[S:17][CH:18]=[C:14]([CH3:13])[N:15]=1)(=[O:21])=[O:20])[CH3:4]
Reactant: Cc1csc(S(=O)(=O)Cl)n1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc(C)cs1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 4-methyl-thiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 7.68 (s, 1H), 4.07 (q, 2H), 3.26 (s, 2H), 3.02 (t, 2H), 2.58 (t, 2H), 2.43 (s, 3H), 1.18 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: Cc1ccc2nc(Nc3nc4cc(C(=O)O)ccc4n3C)sc2c1
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C)cc3s1)n2C

Procedure:
2-(6-Methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (29 mg) was prepared by following General Procedure F using 2-(6-methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 397.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccccc3)c12
Reactant: c1nc[nH]n1
Product: Cc1csc2nc(-n3cncn3)nc(NCc3ccccc3)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]1B(O)O.[F-].[K+].[Br-]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1COCC1>[C:17]([C:16]1[N:12]([CH3:11])[C:13]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[CH:4][CH:3]=2)=[CH:14][CH:15]=1)#[N:18]
Reactant: N#CNc1ccc(Br)cc1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1-c1ccc(NC#N)cc1
Yield: 33.7 %

Procedure:
4-bromophenylcyanamide (0.651 g, 3.34 mmol), tris(dibenzylideneacetone)dipalladium (76 mg, 0.078 mmol), N-methyl-5-cyanopyrroleboronic acid (1.1 g, 7.3 mmol), and potassium fluoride (0.776 g, 13.2 mmol) were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen and THF (10 mL) was added. tri-Tert-butylphosphine (10 wt % in hexane) (0.486 mL, 0.078 mmol) was added to the mixture and allowed to stir 3 hours at 50° C. until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/ethylacetate, filtered through a plug of silica gel, the solvent was evaporated and the residue was flash chromatographed using 5/1, 4/1, then 3/2 Hexane/Ethylacetate to give (0.250 g, 33%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([Cl:20])[C:14]=2[Cl:21])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[C:15]([Cl:20])[C:14]=2[Cl:21])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: Cn1nc(Cc2ccc(O)c(Cl)c2Cl)c(Cl)c1OC(F)F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cc2nn(C)c(OC(F)F)c2Cl)c(Cl)c1Cl

Procedure:
A solution of 0.6 g (1.7 mmol) of 4-[(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)methyl]-2,3-dichlorophenol, 0.35 g (2.5 mmol) of potassium carbonate, 0.42 g (2.5 mmol) of potassium iodide and 0.39 g (2.5 mmol) of methyl bromoacetate in 30 ml of dimethylformamide was stirred for 16 hours and then admixed with 20 ml of water. The aqueous phase was subsequently extracted with 100 ml of diethyl ether. The extract was washed with water, dried over sodium sulfate and finally concentrated. Yield: 0.4 g;
Reaction SMILES: [CH3:1][O:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[Li+].CCC[CH2-].[CH:14]([S:22](Cl)(=[O:24])=[O:23])=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCCCCC>[CH:14]([S:22]([N:7]1[CH:3]([O:2][CH3:1])[CH2:4][CH2:5][C:6]1=[O:8])(=[O:24])=[O:23])=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: COC1CCC(=O)N1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1CCC(=O)N1S(=O)(=O)C=Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
3.29 g of 5-methoxy-2-oxo pyrrolidine (SYNTHESIS 4, 315-17 (1980)) is dissolved in 100 cm3 of anhydrous tetrahydrofuran. After cooling to -20° C. 17.86 cm3 of a 1.6M solution of N-butyllithium in hexane is a while keeping the temperature at about -30° C. The mixture is agitated for 30 minutes at -35° to -30° C., then a solution of 5.80 g of styrenesulphonyl chloride (CA 47, 3262c, 1953) in 14 cm3 of anhydrous tetrahydrofuran is added slowly. After allowing this to return to ambient temperature, the solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and n-hexane (1--). The product obtained is crystallized from isopropanol, and 3 g of the expected product is obtained. m.p. 98°-99° C.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:31]12[C:38](=[O:39])[O:37][C:35](=[O:36])[C@@H:32]1[CH2:33][CH2:34]2>>[CH2:1]([N:8]([CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH2:10]1)[C:38]([CH:31]1[CH2:34][CH2:33][CH:32]1[C:35]([OH:37])=[O:36])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nc(COCC3CCCC(NCc4ccccc4)C3)c(C)o2)c1
Reactant: O=C1OC(=O)[C@@H]2CC[C@H]12
Product: Cc1cccc(-c2nc(COCC3CCCC(N(Cc4ccccc4)C(=O)C4CCC4C(=O)O)C3)c(C)o2)c1

Procedure:
Analogous to the reaction conditions of example 1, benzyl-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexyl]amine and cis-cyclobutane-1,2-dicarboxylic anhydride give 2-{benzyl-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexyl]carbamoyl}cyclobutanecarboxylic acid. C32H38N2O5 (530.67), MS (ESI): 531 (MH+).