Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:40]1[CH:41]=[CH:42][C:43]2[N:44]([N:46]=[C:47]([NH2:49])[N:48]=2)[CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCO.O1CCOCC1>[C:12]([NH:11][S:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:40]2[CH:41]=[CH:42][C:43]3[N:44]([N:46]=[C:47]([NH2:49])[N:48]=3)[CH:45]=2)[CH:3]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Reactant: Nc1nc2ccc(Br)cn2n1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2ccc3nc(N)nn3c2)c1
Temperature: 120 °C
Yield: 184.5 %

Procedure:
5-bromo-N-tert-butylpyridine-3-sulfonamide (375 mg, 0.986 mmol), bis(pinacolato) diboron (276 mg, 1.085 mmol), potassium acetate (290 mg, 2.96 mmol), [1,1′bis(diphenylphosphino)ferrocene]dichloro-palladium (II) complex with CH2Cl2 (40 mg, 0.049 mmol) and dioxane (3 ml) were heated to 120° C. for 60 minutes in the microwave. After this time aryl bromide (A) (147 mg, 0.69 mmol), Na2CO3 (2M aqueous solution, 2 mL), EtOH (0.4 ml) and a further portion of [1,1′bis(diphenylphosphino)ferrocene]dichloro-palladium (II) complex with CH2Cl2 was added and reaction mixture heated further for 60 minutes at 120° C. in the microwave. After this time the solvents were removed in vacuo and the brown residue redissolved in 2M HCl (30 mL), the aqueous phase was washed with ethyl acetate (3×20 mL) and then neutralized with concentrated NaOH to pH 7.0. The aqueous phase was then extracted with ethyl acetate (3×20 mL), the organic extracts were combined, dried over sodium sulfate, filtered and the solvent removed in vacuo to afford the desired product as a brown solid (441 mg, 54%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:6]=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:22]1([CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:19]([NH:1][C:2]2[N:3]=[N:4][N:5]([CH2:7][C:8]([F:9])([F:11])[F:10])[N:6]=2)=[O:20])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Nc1nnn(CC(F)(F)F)n1
Product: O=C(Nc1nnn(CC(F)(F)F)n1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 146-148 and MS: (neg. ions): m/e=360.0 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-(2,2,2-trifluoroethyl)-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(O)[C@H](O)[C@@H](O)[C@H](O)C(C(O)=O)=O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
This example describes results using a plug flow reactor for preparation of L-ascorbic acid from 2-keto-L-gulonic acid. A solution of 2-KLG was obtained by fermentation of glucose using genetically modified Pantoea citrea followed by partial purification via microfiltration, electrodialysis, and subsequent crystallization which provides the monohydrate of 2-keto-L-gulonic acid. An aqueous solution of 2-KLG was prepared from this material by dissolving 110 g the monohydrate obtained above in 890 mL of water. The resultant solution contained 10.41 wt. % 2-KLG and 0.05 wt. % L-ascorbic acid by analysis. This solution was used as feedstock throughout this experiment.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[CH:20]=1.[Br:21]Br>C(O)(=O)C>[Br:21][C:5]1[C:4]([O:3][CH3:2])=[CH:20][C:8]2[CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][NH:11][CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: BrBr
Reactant: COc1ccc2c(c1)C(c1ccccc1)CNCC2
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc2c(cc1Br)CCNCC2c1ccccc1

Procedure:
8-Methoxy-1-phenyl-2,3,4,5-tetrahydro-1H3-benzazepine hydrochloride (66 g, 0.23 m) was suspended in acetic acid (300 ml) and treated with bromine (43 g, 0.27 m). The mixture was heated to 95° for one hour, cooled and filtered. The filter cake was partitioned between ethyl acetate and ammonium hydroxide to afford 7-bromo-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12]C)=[C:10]([CH3:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.B(Br)(Br)Br.CO>C(Cl)Cl>[Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1c(C)cc2ncccc2c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2ncccc2c(Br)c1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To the solution of 5-bromo-6-methoxy-7-methylquinoline (6.5 g, 25.8 mmol) in DCM (150 mL) was added BBr3 slowly (77.3 mL, 1.0 M in DCM, 77.3 mmol). The mixture was stirred for 3 hours and cooled to 0° C. Methanol (40 mL) was added slowly and the mixture was stirred for 20 minutes. The solvents were removed under reduced pressure. The solid was dissolved in methanol (100 mL) and was treated with 1.0 N sodium hydroxide solution (50 mL) (pH ˜12). The mixture was stirred for 12 hours and acetic acid was added to adjust pH to between 4-5. The mixture was filtered and washed with water. The gray solid was dried under reduced pressure to give 5-bromo-7-methylquinolin-6-ol (5.0 g). LCMS-ESI+ (m/z): 238.2, 240.1 (M+H)+, 236.1, 238.0 (M−H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42]CC2C=CC=CC=2)[C:35]=1[C:36]#[N:37]>>[C:36]([C:35]1[C:38]([OH:42])=[CH:39][CH:40]=[CH:41][C:34]=1[O:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:25](=[O:27])[CH2:24][CH2:23][C:11]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:21])=[O:22])=[C:9]([OH:8])[CH:10]=1)#[N:37]
Reactant: N#Cc1c(OCCCCN)cccc1OCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Product: N#Cc1c(O)cccc1OCCCCNC(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared using (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid and 2-(4-aminobutoxy)-6-benzyloxybenzonitrile analogous to Example 100 steps C and D: (M−1)−=487. HPLC retention time: 0.82 min. (Method A).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:7]2[C:12]([C:13]=1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1)=[CH:11][CH:10]=[C:9]([O:26][CH3:27])[CH:8]=2)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[CH2:16][NH:15][C:14]([C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:26][CH3:27])=[CH:10][CH:11]=2)[N:6]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:5]=1[C:3]([OH:4])=[O:2])=[O:25]
Reactant: COC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC)cc2n1Cc1ccccn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(=O)O)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
General Procedure L. To a solution of methyl3-(3,4-difluorobenzylcarbamoyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 93, 149 mg, 0.32 mmol) in CH2Cl2 (10 ml) was added BBr3 (1M in CH2Cl2, 1.6 ml, 1.6 mmol) slowly at 0° C. The mixture was stirred at room temperature for 2 h, and was quenched with ice, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by PTLC on silica gel (10% MeOH—CH2Cl2) to yield the title compound.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:18])=[O:2])=[N:12][CH:13]=1
Reactant: COC(=O)c1cccc(Nc2ccc(Cl)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A mixture of 3-(5-chloro-pyridin-2-ylamino)-benzoic acid methyl ester (315 mg, 1.2 mmol) and NaOH (200 mg, 5.0 mmol) in methanol:THF:water (1:1:1, 3 mL) was stirred at room temperature for 8 h. Solvents were evaporated. Crude mass was taken in water (40 mL), acidified to pH 4.0 and extracted with ethyl acetate to obtain 3-(5-chloro-pyridin-2-ylamino)-benzoic acid (238 mg).
Reaction SMILES: Br[CH:2]([C:4]1[N:13]([CH2:14][CH2:15][CH3:16])[C:12](=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:28]2[CH2:33][CH2:32][N:31]([CH:2]([C:4]3[N:13]([CH2:14][CH2:15][CH3:16])[C:12](=[O:17])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH3:3])[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Reactant: CCCn1c(C(C)Br)nc2ccccc2c1=O
Solvent: CCO
Product: CCCn1c(C(C)N2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2)nc2ccccc2c1=O
Yield: 13.5 %

Procedure:
A mixture of 2-(1-bromo-ethyl)-3-propyl-3H-quinazolin-4-one (30 mg, 0.1 mmol) and 1-(4-bromo-benzenesulfonyl)-piperazine (47 mg, 0.15 mmol) in ethanol (1 mL) was refluxed overnight. The reaction mixture was then concentrated in vacuo and purified by reverse phase HPLC to yield the product as a white powder (7 mg, 9%). 1H NMR (CDCl3) δ 1.03 (t, 3H, J=5.8 Hz), 1.72 (sex, 2H, J=6.0), 1.80 (d, 3H, J=5.2), 3.48 (m, 6H), 3.90 (m, 3H), 4.23 (m, 1H), 4.77 (q, 1H, J=5.2 Hz), 7.58 (m, 3H), 7.68 (d, 1H, J=6.5 Hz), 7.72 (d, 2H, J=7.1 Hz), 7.81 (t, 1H, J=6.2 Hz), 8.28 (d, 1H, J=6.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)NC2CC2)cn1
Yield: 28 %

Procedure:
As described for example 2b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using cyclopropylamine instead of aminomethylcyclopropane, to the title compound (SiO2, heptane:ethyl acetate=90:10 to 60:40, 32 mg, 28%) which was obtained as a white solid. MS: m/e=351.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].C(OCC)C>[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
Chlorobenzene (1130 mg, 10 mmoles, 1.090 ml) NiBr2 (438 mg, 2 mmoles) and NaI (1650 mg, 11 mmoles) were placed in a dry, degassed, airtight flask and were slurried in DMF (20 ml). The mixture was placed in a 140° C. oil bath for 4 to 5 h during which time it darkened to blue-green or deep red. The solution was cooled to room temperature and ethyl acrylate (1100 mg, 11 mmoles, 1.190 ml), triethylamine (Et3N) (1111 mg, 11 mmoles, 1.530 ml), tri-o-tolyl phosphine (P(otol)3) (1216 mg, 4 mmoles) and palladium dibenzylideneacetone (Pd(dba)2) (29 mg, 0.05 mmoles) were added. A cold finger condenser was affixed under a slow argon flow. The mixture was heated overnight in a 140° C. oil bath, typically 15 to 17 h. The mixture was cooled and mixed with about 100 ml diethyl ether (Et 2 O) to precipitate inorganic salts. If the mixture was to be analyzed by gas chromatography (GC) undecane (0.700 ml) was added as an internal standard. The coupling product was isolated by filtering the Et2O slurry through a 2"×2"(5.08 cm×5.08 cm) silica gel bed packed in a fritted funnel. The crude material was eluted with an additional 200 to 250 ml Et2O. The combined Et2O fractions were washed three times with 15 ml aqueous saturated NaCl solutions, dried over MgSO4, filtered and the solvent removed on the rotary evaporator. Radial chromatography (silica gel, 5:1 volume mixture of hexane and Et2O) afforded 1120 mg (65 mole % yield) of ethyl cinnamate as a yellow oil.
Reaction SMILES: C(OC(N=NC(OCC)=O)=O)C.[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:43]([O:50][CH2:51][CH2:52][CH2:53][CH2:54]O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.CCCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:54][CH2:53][CH2:52][CH2:51][O:50][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCCCOCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of 14.36 g (82.5 mmol) of diethyl-azo-dicarboxylate in 50 ml of tetrahydrofuran was added within 30 minutes to a solution of 11.4 g (75.0 mmol) 4-hydroxy-benzoic acid methyl ester, 20.65 g (78.8 mmol) of triphenylphosphin and 13.5 g (75.0 mmol) of 4-benzyloxy-1-butanol dissolved in 100 ml of tetrahydrofuran. The reaction mixture was then stirred for 1 hour at room temperature, 1 g of triphenylphosphin was added and stirring continued for 1 hour at room temperature and for 30 minutes at reflux. The reaction mixture was then diluted with 200 ml of hexane and filtered. The filtrate was poured into 200 ml of a saturated potassium carbonate solution and extracted 3 times with 200 ml of ethylacetate. The combined ethylacetate phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 98:2 v/v mixture of dichloromethane and ether as the eluent giving 21.8 g (92.4%) 4-(4-benzyloxy-butoxy)-benzoic acid methyl ester as colorless viscous oil, MS: 314 (M+).
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:25][CH:24]=3)[CH2:18]2)=[O:14])=[CH:10][CH:9]=1.O>C(Cl)Cl>[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]4=[O:36])=[CH:25][CH:24]=3)[CH2:18]2)=[O:14])=[CH:10][CH:9]=1
Reactant: O=C(CCCCCl)Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCCCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
30 mg of 60 percent NaH in liquid paraffin are added under inert conditions to 5 ml of DMSO, and the mixture is heated at 75° C. for 30 min until gas evolution ceases. Then a solution of 290 mg (0.617 mmol) of 5-chloro-N-[((5S)-3-{4-[(5-chloropentanoyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide (from Example 161) in 5 ml of methylene chloride is added dropwise, and the mixture is stirred at room temperature overnight. The reaction is stopped and the mixture is added to 100 ml of water and extracted with ethyl acetate. The evaporated organic phase is chromatographed on an RP-8 column and eluted with acetonitrile/water. 20 mg (7.5% of theory) of the target compound are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[NH2:17][CH2:18][C:19]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[O:20].C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:17][CH2:18][C:19]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[O:20])=[N:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CCCN(CCC)C(=O)CN
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCCN(CCC)C(=O)CNc1nc(-c2ccccc2)ncc1[N+](=O)[O-]
Yield: 96.7 %

Procedure:
A mixture of 4-chloro-5-nitro-2-phenylpyrimidine (6.0 g), 2-amino-N,N-dipropylacetamide (6.0 g), triethylamine (5.2 g) and isopropanol (70 ml) is refluxed for six hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added chloroform and water. The chloroform layer is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give the desired compound (8.8 g), m.p. 142-143° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:11][C:10]([CH3:12])=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:7]=1[C:24](=[O:41])[NH:25][CH2:26][CH2:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[I-].[Na+].[N-:44]=[N+]=[N-].[Na+].CN(C=O)C>CC(O)C.C(OCC)(=O)C>[NH2:44][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:11][C:10]([CH3:12])=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:7]=1[C:24](=[O:41])[NH:25][CH2:26][CH2:27][CH:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)C1=C(C)NC(COCCCl)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C1c1cccc(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(COCCN)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C1c1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
0.12 g (0.20 mmol) of methyl 6-(2-chloroethoxy)methyl-4-(3-chlorophenyl)-5-(3,3-diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylate and 0.030 g (0.20 mmol) of sodium iodide were dissolved in 2 ml of 2-propanol, and the obtained solution was stirred at 70° C. for 24 hours. The solvent was evaporated under reduced pressure. Dichloromethane was added to the residue, and sodium iodide thus precipitated was separated by the filtration. The filtrate was treated under reduced pressure, and 15 mg (0.23 mmol) of sodium azide and 2 ml of DMF were added thereto. The reaction mixture was stirred at 50° C. for 16 hours. Ethyl acetate was added thereto. After washing with water and saturated aqueous sodium chloride solution, the organic layer was concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=7/3) to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:16]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([C:15]=2[C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([O:26][S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:35][CH:34]=2)[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C(=O)Cl)cc2)cc1
Reactant: c1ccc(-c2cc3ccccn3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C(=O)c3c(-c4ccccc4)cc4ccccn34)cc2)cc1
Reaction time: 12 h
Yield: 52.3 %

Procedure:
In a flask, containing a solution of 6.5g (0.044 mol) of 2-phenylindolizine in 100 ml of dichlorethane, 12.4 g (0.04 mol) of 4-tosyloxy-benzoyl chloride were added at room-temperature. The mixture was stirred for 12 hours and then poured into a 10%-solution of sodium carbonate. The product which precipitated was washed to neutrality and recrystallized from carbon tetrachloride. In this manner, 2-phenyl-3-(4-tosyloxy-benzoyl)-indolizine was obtained in a yield of 52.3%. M.P. 177°-178° C.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]([CH2:47]OCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:9]=1/[CH:42]=C\OCC.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].O>>[C:23]1([C:20]2[N:19]=[CH:18][C:17]([C:16]3[CH:15]=[N:14][N:13]4[C:8]5[NH:7][CH:47]=[CH:42][C:9]=5[C:10]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[N:11][C:12]=34)=[CH:22][CH:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]
Reactant: CCO/C=C\c1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ccc(-c3cnn4c3nc(C3CCNCC3)c3cc[nH]c34)cn2)cc1
Reaction time: 8 h

Procedure:
(Z)-tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(2-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-15a, 330 mg) was treated with TFA/water (1:1, 4 mL), stirred overnight, concentrated and lyophilized to provide the title compound as a TFA salt
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:11])[C:7](Cl)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:12][S-:13].[Na+]>C(O)(C)(C)C.O.CCOCC>[C:1]([C:4]1[CH:5]=[C:6]([Cl:11])[C:7]([S:13][CH3:12])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOCC
Product: CSc1ncc(C(C)=O)cc1Cl
Temperature: 25 °C
Yield: 92.6 %

Procedure:
5-Acetyl-2,3-dichloropyridine (24.5 g, 0.129 mol) was slurried in t-butanol (200 mL) and sodium methanethiolate (10 g, 0.143 mol) was added. The mixture was heated under reflux conditions for two hours, cooled to room temperature, and diluted with water (200 mL) and ether (150 mL). This was separated and the aqueous phase extracted with ether (50 mL). The combined organic extracts were washed with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulphate, and evaporated to dryness to give the desired product (24.1 g, 94%) as a pale, low melting solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@H:3]1[NH:14]C(=O)OC(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:14][C@@H:3]1[CH2:4][C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[C:2]1([CH3:22])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCOCC2)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCOCC1
Reaction time: 1 h

Procedure:
Tert-butyl (1R,3S)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutylcarbamate (Step 1, 0.260 g, 0.833 mmol) was taken in TFA:DCM (1:4) (3 ml) at 0° C.-room temperature and stirred for 1 hour. After completion of the reaction the solvent was evaporated and the crude dissolved in DCM and basified with Et3N (0.7 ml, 5.0 mmol). The resulting solution as such used for next reaction immediately. Wt: 0.176 g.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([OH:3])=[O:2].O.[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1>C(O)C>[C:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])([O:3][CH2:14][CH3:15])=[O:2]
Reactant: O=C(O)CCCC1CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCC1CCCC1=O

Procedure:
In the manner described in Example 3, treatment of 2-(3-carboxypropyl)cyclopentan-1-one (Example 5) with p-toluenesulfonic acid monohydrate in ethanol gives a colorless oil, b.p. 93° C. (0.10 mm).