Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[CH:13][N:12]([C:15]3[S:16][C:17]([C:27]([NH2:29])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=4)[N:19]=3)[C:11]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([C:18]2[N:19]=[C:15]([N:12]3[C:11]4[CH:30]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]5[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]5)[CH:8]=[CH:9][C:10]=4[N:14]=[CH:13]3)[S:16][C:17]=2[C:27]([NH2:29])=[O:28])[CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCCCl)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(CCCCOc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Reaction time: 3 h
Yield: 68.6 %

Procedure:
A mixture of 0.023 g (0.05 mmole) of 2-[6-(4-chloro-butoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.37a), 0.5 mL of dimethylformamide, 0.035 g (0.25 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.017 mL (0.15 mmole) of 1-methyl-piperazine was stirred at 100 degrees for 3 hours. The mixture was concentrated under reduced pressure, and diluted with 20 mL of water. The precipitate was collected by filtration and the solid triturated with diethyl ether to give 0.018 g of 4-(3-chloro-phenyl)-2-{6-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzoimidazol-1-yl}-thiazole-5-carboxylic acid amide (I.37) as a white powder. MH+/Z=525
Reaction SMILES: [H-].[Na+].[C:3]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]([OH:45])[CH:41]=[C:42]([OH:44])[CH:43]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>C1COCC1.CN(C=O)C>[CH2:62]([O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:45][C:40]1[CH:39]=[C:38]([O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][C:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:43]=[C:42]([O:44][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:41]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: Oc1cc(O)cc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: BrCCOCCOCCOCCOCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(COCCOCCOCCOCCOCCOc2cc(OCCOCCOCCOCCOCCOCc3ccccc3)cc(OCCOCCOCCOCCOCCOC(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 118.7 %

Procedure:
To an ice-cooled mixed suspension of sodium hydride (350 mg, 8.8 mmol; 60% in mineral oil) in THF (4.5 ml) and DMF (1.5 ml), a mixed solution of Compound 45 (1.0 g, 1.7 mmol) in THF (4.5 ml) and DMF (1.5 ml) was gradually added, and this was followed by stirring for 30 minutes. A solution of Compound 20 (2.7 g, 6.8 mmol) in THF (4 ml) was added thereto, and this was followed by stirring for 20 minutes. After the ice bath was removed, stirring was further conducted at room temperature for 4 hours. After the product was again immersed in the ice bath, water was carefully added to stop the reaction, and this was followed by concentration under reduced pressure. Extraction from ethyl acetate was conducted, and the combined organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. Filtration and concentration under reduced pressure were conducted, after which the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate-ethyl acetate:methanol 19:1)) to yield Compound 46 (light-yellow oil 1.22 g, 59%).
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:33]([O:35][CH3:36])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CCCC(OCC)=O)CCOC1C=CC(CCC(O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH:27]([OH:32])[C:28]([F:29])([F:31])[F:30])=[CH:23][CH:24]=2)[CH2:15][C@H:14]1[C:33]([O:35][CH3:36])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(/C=C/C(O)C(F)(F)F)cc2)C[C@H]1C(=O)OC
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(O)C(F)(F)F)cc1
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(CCC(O)C(F)(F)F)cc2)C[C@H]1C(=O)OC
Yield: 99 %

Procedure:
(2S, 4S)-1-N-Dodecyl-4-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1-yl]phenoxy]pyrrolidine-2-carboxylic acid, methyl ester (552 mg., 1.07 mmol) was hydrogenated as described in the preparation of 4-[N-dodecyl-N-2-[4-[3-hydroxy-4,4,4-trifluorobutyl]phenoxy] ethylamino]-butanoic acid, ethyl ester and afforded the title compound (546 mg, 99%) as a clear oil. [a]D=−89.0° (c 0.4, CHCl3)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][CH:60]([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[O:24][CH2:61][CH:60]([F:63])[F:59])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reactant: OCC(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: FC(F)COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.5 %

Procedure:
To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (183 mg, 0.433 mmol), 1,1′-(azodicarbonyl)dipiperdine (219 mg, 0.868 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.217 mL, 0.869 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2-difluoroethanol (0.272 mL, 4.30 mmol) was added to the reaction mixture. The mixture was stirred at 50° C. for 14 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (102 mg, 0.21 mmol, 48%) as colorless crystals.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C(O[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)C>C1COCC1.C(OCC)(=O)C>[CH3:21][N:19]([CH3:20])[C:16]1[CH:15]=[CH:14][C:13]([C:12](=[O:22])[CH2:2][C:1]#[N:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc(N(C)C)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=O)CC#N)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.9 mL) in 25 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then treated in dropwise fashion with 14.3 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 1 h and subsequently treated in dropwise fashion with a solution of 5 gms. of 4-dimethylamino-benzoic acid ethyl ester in 25 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is diluted with ethyl acetate and then extracted with 10% NaOH(aq). The aqueous layer is acidified (pH 6-7) with a 1 M HCl(aq) solution affording a white precipitate. The precipitate is filtered and washed with water. The filtrate is then extracted ethyl acetate. The organic layer is concentrated in vacuo. The organic extraction yields very little of the expected 3-(4-dimethylamino-phenyl)-3-oxo-propionitrile, however, the precipitate isolated from the acidification of the original aqueous layer is indeed the desired 3-(4-dimethylamino-phenyl)-3-oxo-propionitrile. Upon drying the precipitate in vacuo, the desired 3-(4-dimethylamino-phenyl)-3-oxo-propionitrile is isolated as a light brown solid in the amount of 3.295 gms. (68% yield).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[N:4]=1.Cl.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:37]2[N:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)[CH2:31]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([NH:36][C:37]3[N:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[CH2:31]2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(N4CCCC(Nc5ccc(C#N)cn5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 53A), 60.9 mg (0.25 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 19A) and 0.21 ml (1.23 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 39 mg (33% of theory) of the product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.[CH3:19][C:20]([S:23]([NH2:26])(=O)=[O:24])([CH3:22])[CH3:21]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[N:26][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a solution of 6-bromo-2-phenylchroman-4-one (2.010 g, 6.63 mmol) and 2-methyl-2-propane sulfonamide (804 mg, 6.63 mmol) in anhydrous THF (22 mL) is added Ti(OEt)4 (3.025 g, 2.80 mL, 13.22 mmol). The resulting mixture is heated to reflux for 20 h. Brine (10 mL) is added after the mixture is cooled to rt, and stirred vigorously for 10 min. The mixture is filtered through a pad of Celite, and washed with ethyl acetate (50 mL). The filtrate is washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue is purified through chromatography on silica gel to afford N-(6-bromo-2-phenylchroman-4-ylidene)-2-methylpropane-2-sulfinamide 1.05 g, 39%) as a light yellow solid. MS ESI+ve m/z 406 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:20]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1cccc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
To a solution of 3-trifluoromethyl-phenylamine (1 eq.) and ethyl 4-bromobutyrate (2 eq.) in DMF were added K2CO3 (3 eq.) and KI (cat.). The mixture was heated at 100° C. for 16 h, water and EtOAc were added, the organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 90/10 to 70/30) to afford 4-(3-trifluoromethyl-phenylamino)-butyric acid ethyl ester as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[NH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[OH:22].CCN(C(C)C)C(C)C>C(O)C>[OH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:17]1[NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N[C@H]1CCC[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1N[C@H]1CCC[C@@H]1O
Temperature: 60 °C
Yield: 72.8 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.4 g, 6.0 mmol), (1S,2S)-2-aminocyclopentanol hydrochloride (0.7 g, 6.9 mmol) and DIEA (1.0 g) in ethanol (20 mL) was heated at 60° C. for 15 h. After being cooled to room temperature, the reaction solution was concentrated and the residue was purified on silica gel column (eluting with 0-10% ethyl acetate in petroleum ether) to give ethyl 4-((1S,2S)-2-hydroxycyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate (1.3 g, 4.37 mmol, yield 73%) as a white solid. MS (ESI): m/z 298.5 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([O:19]CC)=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C(O)C.C1COCC1.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ncccc1Nc1cc(C(C)(C)C)nn1-c1c(C)cccc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1cccc(C)c1-n1nc(C(C)(C)C)cc1Nc1cccnc1C(=O)O
Temperature: 40 °C
Yield: 84.6 %

Procedure:
To a solution of ethyl 3-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxylate (2.10 g, 5.35 mmol) in a mixture of ethanol (5 mL) and THF (5 mL) was added lithium hydroxide monohydrate (1.12 mg, 26.8 mmol) in water (10 mL), and the mixture was then heated to 40° C. for 1 h. The reaction mixture was cooled to rt, the pH of the solution was adjusted to 5 by addition of 0.5 N hydrochloric acid, and the mixture was concentrated to dryness. The crude mixture was redissolved in methanol and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 1.65 g (85%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 10.22 (br, s, 1H), 9.52 (s, 1H), 8.03 (dd, 1H), 7.86 (dd, 1H), 7.50 (dd, 1H), 7.30 (dd, 1H), 7.18 (d, 2H), 2.02 (s, 6H), 1.37 (s, 9H); ES-MS m/z 321.3 (MH+); HPLC RT (min.) 2.56.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][Mg]Cl.ClC1C=C(C=CC=1F)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>[Pd]>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Fc1cccc(C[Mg]Cl)c1
Agent: [Pd]
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1ccc(F)c(Cl)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(F)c1
Reaction time: 2 h

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.79 mmol) was reacted with 3-fluorobenzylmagnesium chloride (0.25 M in diethyl ether, 52 mL, 13 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3-fluorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6. In this example, Degussa type, 5% palladium on carbon (0.100 g, 0.1 mmol) was used, and the reaction placed under a hydrogen atmosphere in a Parr shaker (40 PSI) for 2 hours. Purification by column chromatography (Isco CombiFlash) eluting with a gradient of 0-40% EtOAc/heptane afforded the title compound. 0.075 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03-2.11 (m, 1H), 2.47-2.56 (m, 1H), 2.59-2.73 (m, 2H), 2.78 (d, J=7.4 Hz, 2H), 3.24-3.32 (m, 1H), 3.81 (s, 3H), 6.39 (d, J=1.7 Hz, 1H), 6.90-7.00 (m, 3H), 7.20-7.35 (m, 1H), 8.94 (br s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:22])/[CH:16]=[C:17](\[NH2:21])/[CH2:18][O:19][CH3:20])[CH3:13].[CH2:23]([O:25][C:26](=[O:35])[CH2:27][C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=O)[CH3:24]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:35])=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:21][C:17]=1[CH2:18][O:19][CH3:20])=[O:22])[CH3:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: CCOC(=O)/C=C(\N)COC
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(COC)N1

Procedure:
After heating a solution of 15.1 g of 3-nitrobenzaldehyde, 16 g of β-amino-γ-methoxycrotonic acid ethyl ester and 19 g of oxalacetic acid diethyl ester in 60 ml of ethanol under reflux for 12 hours, the mixture is evaporated in vacuo and 2-methoxymethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5,6-tricarboxylic acid triethyl ester is obtained in almost quantitative yield, in the form of a yellow oil (nD50 =1.5353).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:10]([CH3:11])[C:9]2[CH:12]=[CH:13][C:14]([N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=3)[CH3:17])=[CH:15][C:8]=2[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)(=[O:28])=[O:27]>>[ClH:24].[C:1]([NH:5][C:6]1[N:10]([CH3:11])[C:9]2[CH:12]=[CH:13][C:14]([N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([CH2:29][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:31][CH:32]=4)[N:19]=3)[CH3:17])=[CH:15][C:8]=2[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(c1ccc2c(c1)nc(NC(C)(C)C)n2C)c1ccnc(Cl)n1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Product: CN(c1ccc2c(c1)nc(NC(C)(C)C)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N2-tert-butyl-N5-(2-chloro-pyrimidin-4-yl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (69 mg, 0.20 mmol) and 4-[(methylsulfonyl)methyl]aniline (37 mg, 0.20 mmol) as a white solid (111 mg, 95%). 1H NMR (300 MHz, d6-DMSO) δ 9.28 (s, 1H), 7.77-7.79 (m, 3H), 7.24 (d, J=8.4 Hz, 3H), 7.16 (d, J=1.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.21 (br s, 1H), 5.67 (d, J=6.0 Hz, 1H), 4.35 (s, 2H), 3.54 (s, 3H), 3.45 (s, 3H), 2.86 (s, 3H), 1.47 (s, 9H) ppm. MS (ESI) m/z=494 [M+H]+.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH:3]([C:14]([O:16][CH3:17])=[O:15])[NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[C:18]([Cl:26])(=O)[C:19]1C=CC=C[CH:20]=1.C(N(CC)CC)C.[CH2:34]1[CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:26][C:18]1[CH:36]=[CH:35][C:34]([C:38]([N:2]2[CH:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[CH2:1]2)=[O:37])=[CH:20][CH:19]=1
Reactant: COC(=O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)c1ccc(Cl)cc1

Procedure:
A mixture of methyl 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (6.9 g, 30 mmol), benzoylchloride (4.2 g, 30 mmol) and triethylamine (4.8 mL) in anhydrous THF (150 mL) was refluxed for 9 h. It was concentrated and diluted with water. The solid precipitated was collected by filtration, the solid cake was washed successfully with water and hexane and dried to give methyl 2-(4-chlorobenzoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate, 9.0 g (82%); mp 243-244° C. (lit.19 mp 245-246° C.). 1H NMR (DMSO-d6) δ 3.10 (1H, m, CH2), 3.35 (1H, m, CH2), 3.55 and 3.65 (3H, s, COOMe), 4.41 and 5.18 (1H, d, J=17.4 Hz, NCH2), 4.51 and 4.64 (1H, d, J=16.4 Hz, NCH2), 4.88 and 5.82 (1H, d, J=5.4 Hz, CH), 6.96-6.99 (1H, m, ArH), 7.03-7.08 (1H, m, ArH), 7.25-7.32 (1H, m, ArH), 7.42-7.60 (5H, m, 5×ArH), 10.65 and 10.95 (1H, s, exchangeable NH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][CH:3]=1.C1C(C(OO)=[O:18])=CC=CC=1>C(Cl)(Cl)Cl>[CH3:9][C:8]1([CH3:10])[CH:7]2[C:2]3([CH3:1])[O:18][CH:3]3[CH2:4][CH:5]1[CH2:6]2
Reactant: O=C(OO)c1ccccc1
Reactant: CC1=CCC2CC1C2(C)C
Solvent: ClC(Cl)Cl
Product: CC1(C)C2CC3OC3(C)C1C2

Procedure:
in a first stage, epoxidizing α-pinene with a 15-30% solution of perbenzoic acid in chloroform at a temperature between -1° C. and -10° C. to obtain α-pinene epoxide
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C(N(CC)CC)C.[C:28]1([CH2:34][C:35](Cl)=[S:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:35](=[S:36])[CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:5]2[S:4]1
Reactant: S=C(Cl)Cc1ccccc1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=S)Cc3ccccc3)[C@H]2S1
Temperature: -15 °C
Yield: 90.2 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.0 g) was suspended in dried dichloromethane (50 ml) and then dissolved by adding triethylamine (0.72 g) and dimethylamiline (1.9 g) under cooling at -15° C. To a mixture was dropwise added a solution of phenylthioacetyl chloride (2.2 g) in dried dichloromethane (10 ml) under stirring, and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off, ether was added to the residue, after which the precipitated crystals were collected by filtration are dried to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate (3.4 g), mp 140° to 142° C.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[CH:6]1[C:11](O)=[CH:10]C=[C:8](C)[CH:7]=1.CI.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O>[Pd](Cl)Cl.C(O)(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: COC(C)=O
Reactant: Cc1ccc(O)cc1
Agent: Cl[Pd]Cl
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CI
Solvent: CC(=O)O
Product: CC(=O)Oc1ccccc1

Procedure:
A 300-ml autoclave equipped with an agitator was charged with 59.2 g of methyl acetate, 104 g of p-cresol, 1.8 g of palladium chloride, 31.5 g of methyl iodide and 5.8 g of triphenylphosphine, and the reaction was carried out at 195° C. and a carbon monoxide pressure of 28 kg/cm2 gauge (total pressure of 38 kg/cm2 gauge). The yields of acetic acid and phenyl acetate were 95.8% and 95.6%, respectively. The reaction was repeated several times, and the resulting reaction product liquids were collected and used in Example 13.