Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([CH:41]=O)=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.CSCS(C)=[O:47].C1[CH2:53][O:52][CH2:51]C1>[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([CH2:41][C:51]([O:52][CH3:53])=[O:47])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:17][CH:18]=1
Reactant: CSCS(C)=O
Reactant: C1CCOC1
Reactant: O=Cc1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: COC(=O)Cc1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Yield: 30 %

Procedure:
A mixture of compound 4 (8.32 g) and methyl methylthiomethyl sulfoxide (MMTS) (4.5 g) in THF (100 ml) and benzyltrimethyl ammonium hydroxide (40% in methanol; 20 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was taken up in water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. Toluene was added twice and evaporated again. The residue was taken up in methanol (50 ml). HCl gas was bubbled through the mixture, cooled on an ice bath, for 30 minutes. The mixture was stirred overnight. The solvent was evaporated. The residue was taken up in water, alkalized with K2CO3 and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 2.7 g (30%) of methyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-acetate (compound 5).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].Br[C:17]1[S:18][CH:19]=[C:20]([Br:22])[N:21]=1>>[Br:22][C:20]1[N:21]=[C:17]([O:15][CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[N:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[S:18][CH:19]=1
Reactant: Brc1csc(Br)n1
Reactant: CCc1cnc(N2CCC(O)CC2)cn1
Product: CCc1cnc(N2CCC(Oc3nc(Br)cs3)CC2)cn1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42 using 1-(5-ethylpyrazin-2-yl)piperidin-4-ol and 2,4-dibromothiazole (0.480 g, 54%); MS: 369.2 (M+1).
Reaction SMILES: [CH3:1][Mg]Br.CON[C:7]([CH:9]1[CH2:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH3:16])[CH2:10]1)=[O:8].Cl>C(OCC)C.CC1CCCO1>[C:7]([CH:9]1[CH2:10][N:11]([C@H:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH3:16])[C:12](=[O:14])[CH2:13]1)(=[O:8])[CH3:1]
Reactant: CONC(=O)C1CC(=O)N([C@@H](C)c2ccc(OC)cc2)C1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: CC1CCCO1
Product: COc1ccc([C@H](C)N2CC(C(C)=O)CC2=O)cc1
Temperature: 20 °C
Reaction time: 1.25 h

Procedure:
530 mL of a 3 M solution of methylmagnesium bromide in diethylether is added slowly to a cooled solution of 271 g of (R/S)—N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide (mixture of diastereoisomers) in 1.4 L of 2-methyltetrahydrofuran so that the temperature remains under 0° C. After complete addition the temperature is kept for 75 minutes at 0° C. and then warmed up to 20° C. The suspension is stirred 16 hours at 20° C. Under cooling 650 mL of a 4 M hydrochloric acid are added. The organic phase is separated and washed with 500 mL saturated sodium carbonate solution and with 500 mL saturated brine. The organic phase is dried over sodium sulfate. After filtration the solvent is evaporated under reduced pressure.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise benzoyl chloride (0.116 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered and the filtrate was evaporated to 0.498 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.265 g colorless crystals. Mp 130° C. Mass spectrum, m+ =433. Anal (C27H33N5O6) theory C, 61.94; H, 6.35; N, 13.38; found C, 61.73; H, 6.35; N, 13.33.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[O:15][CH3:16]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][C:7]=1[O:15][CH3:16])[NH2:12]
Reactant: COc1ccc([N+](=O)[O-])cc1OCCN(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1OCCN(C)C
Yield: 100 %

Procedure:
A solution of 2-(2-dimethylaminoethoxy)-4-nitroanisole (D10, 11.8 g, 0.049 mole) in ethanol (200 ml) was hydrogenated over 10% Pd-C (1 g) at atmospheric temperature and pressure. The catalyst was filtered off through kieselguhr and the filtrate concentrated in vacuo to afford the title compound as a beige solid (10.3 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([CH:70]([NH2:77])[CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][NH:72]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][CH2:76][CH:71]1[CH2:70][NH2:77])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(C)(C)OC(=O)C(N)C1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(tert.-butyloxycarbonyl-aminomethyl)-piperidine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[C:10]([O-])(=[O:12])C.[Na+].C(O)=O>>[CH:10]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8])=[O:12]
Reactant: CC(=O)[O-]
Reactant: NC(=O)c1cccn1N
Agent: [Na+]
Solvent: O=CO
Product: NC(=O)c1cccn1NC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-Amino-1H-pyrrole-2-carboxamide (1.00 g, 8.0 mmol) and sodium acetate (1.60 g, 20.0 mmol) was added formic acid (11.0 ml, 287 mmol). The mixture was stirred overnight at RT. After removing the excess formic acid in vacuo, water (5 mL) was added and the mixture was cooled to 0° C. The mixture was filtered and the solid washed with water and dried in vacuo to afford 1-formamido-1H-pyrrole-2-carboxamide which was advanced without further purification.
Reaction SMILES: [F:1][S:2]([C:5]1[S:6][C:7](Cl)=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)(=[O:4])=[O:3].C1N2CN3CN(C2)C[N:15]1C3.S(=O)(=O)(O)O>CO>[F:1][S:2]([C:5]1([NH2:15])[CH2:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][S:6]1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)F)sc1Cl
Reactant: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: CO
Product: NC1(S(=O)(=O)F)CC([N+](=O)[O-])=CS1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 2-fluorosulphonyl-4-nitro-5-chlorothiophene (20.4 parts), was added to methanol (240 parts) with hexamine (22.5 parts). Heated to reflux and stirred under these conditions for 4 hours. Cooled to room temperature and poured onto 10% sulphuric acid solution (250 parts). The product was extracted out with ethyl acetate, separated and dried over magnessium sulphate, then screened and concentrated to yield the product 2-fluorosulphonyl-4-nitro-2-aminothiophene (16 parts).
Reaction SMILES: [CH:1]1([C:4](OC)=O)C[CH2:2]1.[Br:8][C:9]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>>[Br:8][C:9]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]1[C:16]([C:17]#[N:18])=[C:15]([CH:4]2[CH2:1][CH2:2]2)[NH:19][C:20]2=[N:21][NH:22][CH:23]=[C:24]12
Reactant: N#Cc1cccc(C=O)c1Br
Reactant: COC(=O)C1CC1
Reactant: Nc1cc[nH]n1
Product: N#CC1=C(C2CC2)Nc2n[nH]cc2C1c1cccc(C#N)c1Br

Procedure:
The title compound was prepared from methyl cyclopropanecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([SH:16])[CH:11]=[C:12]([Cl:15])[C:13]=1[OH:14].[F:17][C:18]([F:31])([F:30])[CH2:19]OS(C1C=CC=CC=1)(=O)=O.Cl>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([S:16][CH2:19][C:18]([F:31])([F:30])[F:17])[CH:11]=[C:12]([Cl:15])[C:13]=1[OH:14]
Reactant: O=S(=O)(OCC(F)(F)F)c1ccccc1
Reactant: Oc1c(Cl)cc(S)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1c(Cl)cc(SCC(F)(F)F)cc1Cl
Reaction time: 6 h
Yield: 71.1 %

Procedure:
64 g of potassium carbonate were added to a solution of 41.9 g of 3,5-dichloro-4-hydroxy-benzenethiol in 200 ml of N,N-dimethylformamide under nitrogen atmosphere. To the stirred mixture were dropped at 30° to 40° C. 55 g of 2,2,2-trifluoroethyl-benzenesulfonate. The whole was stirred at 60° to 70° C. for 6 hours, cooled, mixed with 1.5 l of water, and acidified to pH 2 by dropwise addition of hydrochloric acid. A resulted oil was extracted with toluene and the toluene extract was washed with water. The washed toluene extracted was stirred with 160 ml of a 25% aqueous potassium hydroxide solution, and a water layer was separated. Then the separated water layer was acidified to pH 2 by adding hydrochloric acid. A resulted oil was extracted with toluene. The toluene extract was washed with water, dried over anhydrous sodium sulphate, and evaporated to give a residue. The residue was distilled under reduced pressure to give 42.3 g of 2,6 -dichloro-4-(2,2,2-trifluoroethylthio)-phenol which boiled at 85° to 88° C./1 mmHg.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]=[C:7]([CH3:14])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Br:15]N1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:15][C:13]1[CH:12]=[N:11][N:10]2[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][C:7]([CH3:14])=[N:8][C:9]=12
Reactant: Cc1cc(CC(C)C)n2nccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(CC(C)C)n2ncc(Br)c2n1
Temperature: 25 °C

Procedure:
A solution of 7.5 g (0.026 mol) of 7-isobutyl-5-methylpyrazolo-[1,5-a]pyrimidine in 60 ml chloroform was treated with 4.6 gm (0.026 mol) of N-bromosuccinimide. The mixture was stirred at ambient temperature and then allowed to cool overnight in the refrigerator. The mixture was then poured over ice (100 gm), rendered alkaline with 6N NaOH, and extracted with chloroform. The chloroform solution was separated, dried (Na2SO4), and distilled to yield 5.5 gm, (47%) of a light yellow, viscous oil, b.p. 127°-129° /1.5 mm.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:14])[CH:11]([C:29](=[O:30])[NH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]#[N:13])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)Cn1cccc1C(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
The solution of 2.5 g of 1-isobutyl-β-oxo-2-pyrrolpropionitrile in 30 ml of toluene and 1.6 g of triethylamine is treated with 1.6 g of phenylisocyanate while stirring. After standing overnight the mixture is filtered and the residue dissolved in 5% aqueous sodium hydroxide. The solution is filtered, acidified with 5 N hydrochloric acid and extracted with diethyl ether-ethyl acetate. The organic solution is washed with water, dried, evaporated, the residue triturated with ethanol and recrystallized from methanol, to give the 1-isobutyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 134°-136°.
Reaction SMILES: S(O)(O)(=O)=O.N[C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1.N([O-])=O.[Na+].[ClH:22]>>[Cl:22][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1
Reactant: Cl
Reactant: Nc1nnc(-c2ccccc2)s1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Clc1nnc(-c2ccccc2)s1
Temperature: 0 °C

Procedure:
A mixture of 2-amino-5-phenyl-1,3,4-thiadiazole sulphate (10.0 g, 56.4 mmol) and conc. hydrochloric acid (100 ml) was stirred at 0° C. Sodium nitrite (5.06 g, 69 mmol) was added at 0° C. The mixture was stirred for 9 days at room temperature. The crystals were filtered and resuspended in aqueous hydrochloric acid (150 ml, 1M), stirred overnight and filtered. Aqueous sodium hydroxide (100 ml, 4 M) was added and extracted with ethyl acetate. Yield 5.68 g.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>CC(N(C)C)=O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:28]2[NH:18][C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COc1cccc(C=O)c1
Reactant: NC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.8 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.1 g, 0.3 mmol) was added to a solution of 2-aminobenzamide (30) (1.0 g, 7.3 mmol) and 3-methoxybenzaldehyde (34) (1.0 g, 7.3 mmol) in DMAC (20 ml). The mixture was stirred at room temperature for 2 h and then poured into ice water (200 ml). The precipitate was collected, washed with water, then dried and purified by column chromatography (silica gel-ethyl acetate/n-hexane) to afford 43 (70.0 mg, 4.0%) and 61 (1.7 g, 89.0%) as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][C:23]=1[F:32].CCN(C(C)C)C(C)C>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:11][C:4]1[CH:5]=[C:6]([CH2:8][O:9][CH3:10])[CH:7]=[C:2]([F:1])[C:3]=1[C:22]1[N:27]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[CH:24][C:23]=1[F:32]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: COCc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COCc1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Temperature: 120 °C

Procedure:
A mixture of 2-[2,6-difluoro-4-(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.364 g, 1.28 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (0.300 g, 1.28 mmol) and DIPEA (0.67 mL, 3.8 mmol) in 1,4-dioxane (6 mL) and water (0.30 mL) was purged with nitrogen. Bis(tri-tert-butylphosphine)palladium (65.5 mg, 0.128 mmol) was added to the mixture. The resulting reaction mixture was then heated at 120° C. for 40 min. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with 0-50% EtOAc in hexanes) to give methyl 6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylate as a white powder.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.N[CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=O>P(Cl)(Cl)(Cl)=O>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[O:8][C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:19][CH2:20][C:11]=3[N:9]=2)=[CH:3][CH:4]=1
Reactant: NC(=O)c1ccncc1
Reactant: NC1CCc2ccccc2C1=O
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)CCc1nc(-c3ccncc3)oc1-2
Yield: 72 %

Procedure:
The isonicotinamide of 2-amino-1-tetralone (1.14 g, 0.00429 mole) was placed in 12 ml of phosphorus oxychloride (phosphoryl chloride) and refluxed for 19 hours. The amide dissolved during this period of time. The excess reagent was removed under vacuum. The residue was treated with 12 ml of ethanol and 5 ml of water. The mixture was made basic with 10% KOH. On cooling, the product precipitated and was filtered to give 0.77 g (72% yield) of the oxazole, mp 129°-130° C. 1H NMR(δ, CDCl3): 3.10, 4H, A2B2 ; 7.3-7.9, 4H, m; 8.93, 4H, A2B2.
Reaction SMILES: P([O-])(O)(O)=O.[K+].[CH2:7]([O:9][C:10]([CH:12]1[CH2:17][C:16]([CH2:18][CH3:19])=[CH:15][CH2:14][N:13]1C(OCC(Cl)(Cl)[Cl:25])=O)=[O:11])[CH3:8]>O1CCCC1.[Zn]>[ClH:25].[CH2:7]([O:9][C:10]([CH:12]1[CH2:17][C:16]([CH2:18][CH3:19])=[CH:15][CH2:14][NH:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1CC(CC)=CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(CC)=CCN1
Product: Cl

Procedure:
1M Aqueous potassium dihydrogen phosphate solution (70 ml, 70 mmol), then zinc dust (46 g, 700 mmol), were added to a rapidly stirred solution of the product from (b) above (4.76 g, 13.3 mmol) in tetrahydrofuran (220 ml). After 2 hours at room temperature more zinc dust (5 g, 76 mmol) was added and the reaction mixture stirred for a further hour before being filtered. The filter pad was washed with water and tetrahydrofuran, then the bulk of the organic solvent removed from the combined filtrate and washings. The residual mixture was acidified with 2M hydrochloric acid (30 ml), washed with ethyl acetate to remove starting material (2.32 g recovered), neutralised with solid potassium carbonate and extracted with dichloromethane. The combined organic extracts were washed with saturated brine, dried (MgSO4), treated with excess ethereal hydrogen chloride and evaporated under reduced pressure. Purification of the residue by chromatography on silica gel, using dichloromethane:methanol (95:5) as eluent, furnished the title compound (330 mg), as a colourless waxy solid. m/e 184 (M+H)+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH:29]([OH:31])[CH3:30])[CH:20]=[CH:19][C:18]1=2.[C:33]([O:44][CH2:45][CH:46]=[CH2:47])(=[O:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38]([O-])=[O:39])=[CH:36][CH:35]=1.ClCCl.CCCCCC>CN(C)C1C=CN=CC=1.C1COCC1.ClCCl>[CH3:32][C:17]1([CH3:16])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH:29]([O:31][C:38]([C:37]3[CH:41]=[CH:42][C:34]([C:33]([O:44][CH2:45][CH:46]=[CH2:47])=[O:43])=[CH:35][CH:36]=3)=[O:39])[CH3:30])[CH:20]=[CH:19][C:18]1=2
Reactant: CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C=CCOC(=O)c1ccc(C(=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOC(=O)c1ccc(C(=O)OC(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.54 g (7.44 mmol) of dicyclohexylcarbodiimide and 0.91 g of 4-dimethylaminopyridine are added to a solution of 1.73 g (7.44 mmol) of (+)-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl alcohol and 1.54 g (7.44 mmol) of allyl monoterephthalate in 50 ml of THF. The reaction medium is left stirring at room temperature for 3 h. After treatment and chromatography on silica in dichloromethane, 2.42 g (77%) of the expected derivative are isolated in the form of a colorless oil (Rf=0.46; dichloromethane/hexane, 50:50).
Reaction SMILES: [NH:1]([C:8]1[C:13](I)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:1]([C:8]1[C:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: Clc1ncc(I)c(Nc2ccccc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1ncc(/C=C/c2ccccc2)c(Nc2ccccc2)n1
Yield: 13 %

Procedure:
A solution of 4-anilino-2-chloro-5-iodopyrimidine (Method 59, 331 mg, 1 mmol), styrene (130 mg, 1.2 mmol), triethylamine (0.5 ml) and palladium acetate (20 mg) in acetonitrile (10 ml) was heated at 80° C. for 20 hours. The solution was poured into water (100 ml) and the mixture was extracted with ethyl acetate (2×50 ml). The extracts were washed with water (2×50 ml) and saturated sodium chloride (50 ml) and dried. Volatile material was removed by evaporation and the residue was purified by bond elute chromatography, eluting with 10% ethyl acetate in isohexane, to give the product (40 mg). NMR (CDCl3): 6.8 (d, 1H), 7.0 (d, 2H), 7.15 (t, 1H), 7.3-7.45 (m, 5H), 7.5 (d, 2H), 7.6 (d, 2H), 8.2 (s, 1H); MS (MH+): 308, 310.
Reaction SMILES: N1C(C)=CC=CC=1C.[C:9]([S:12][CH:13]1[N:16]([CH:17](Cl)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:32])[CH2:14]1)(=[O:11])[CH3:10].[C:33]1([P:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCOCC>O1CCOCC1>[C:9]([S:12][CH:13]1[N:16]([C:17](=[P:39]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:32])[CH2:14]1)(=[O:11])[CH3:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Product: CC(=O)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
2,6-Lutidine (2.14 g., 20 mmole) was added to a solution of p-nitrobenzyl 2-(4-acetylthio-2-oxo-1-azetidinyl)-2-chloroacetate (5.9 g., 16 mmole) and triphenylphosphine (5.8 g., 22 mmole) in dioxane (80 ml.). The solution was kept at 55° for 18 hours and then concentrated on a rotary evaporator. The residue was partitioned between brine and ethyl acetate and the organic phase was washed with brine, dried and concentrated. The residue was purified by chromatography over silica gel (ethyl acetate:petroleum ether, 1:2 v/v) to give 4.64 g. (48%) of the title ether.