Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C1CCCCC1.Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1.[CH2:20]([C@H:23]1[CH2:27][O:26][CH:25]([C:28]([F:31])([F:30])[F:29])[NH:24]1)[CH2:21][CH3:22]>CCOCC.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH:25]([NH:24][C@@H:23]([CH2:20][CH2:21][CH3:22])[CH2:27][OH:26])[C:28]([F:30])([F:29])[F:31])=[CH:14][CH:15]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCC[C@H]1COC(C(F)(F)F)N1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: O
Product: CCC[C@@H](CO)NC(c1ccc(Br)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
Butyllithium (41 mL of a 2.0M cyclohexane solution) was added at −30° C. to a solution of 1,4-dibromobenzene (19.3 g, 81.89 mmol) in ether (250 mL) over 10 minutes. After 1 hour, a solution of (4S)-4-propyl-2-trifluoromethyloxazolidine (3.00 g, 16.38 mmol) was added in ether (50 mL) over 30 minutes via an addition funnel. After 90 minutes of stirring, water (100 mL) was added. The organic phase was washed with brine (100 mL), dried over MgSO4, filtered, and evaporated to dryness. The residue was purified on a plug of silica gel (10-30% ethyl acetateihexane elution). An approximately 2:1 mixture of diastomers of (2S)-2-[1-(4-bromophenyl)-2,2,2-trifluoroethylamino]-pentan-1-ol at the CF3 residue was observed based on the norvaline methyl triplet at 0.98 ppm (1H NMR).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(=[NH:59])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[C:8]1[C:6]2=[N:7][C:2]([NH2:59])=[CH:3][CH:4]=[C:5]2[N:10]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:9]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Clc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
280 mg of 5-chloro-3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine was dissolved in 8 mL of toluene, added with 73 mg sodium t-butoxide, 180 μl of benzophenone imine, 100 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 56 mg of tris(dibenzylidene acetone)bispalladium, and stirred at 100° C. for 1.5 hours. The reaction solution was allowed to cool to room temperature, the solvent evaporated, and the residue was added with 5 mL of tetrahydrofuran and 0.3 mL of 5N hydrochloric acid and stirred at room temperature for 1 hour. The resultant reaction solution was added with aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3), to afford 220 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:12]=[CH2:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:23]2[CH2:22][CH2:21][CH:20]([CH2:19][O:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[Cl:15])[CH2:25][CH2:24]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Reactant: Clc1ccccc1OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1cncc(CCN2CCC(COc3ccccc3Cl)CC2)n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 10.9 %

Procedure:
After adding 1.16 g of 2-tert-butoxy-6-vinylpyrazine, 860 mg of 4-(2-chlorophenoxymethyl)piperidine hydrochloride and 0.43 g of anhydrous potassium carbonate to 10 ml of N,N-dimethylformamide, the mixture was stirred for 2 days at 100° C. Ice water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (145 mg, 11% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=[O:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:30]3[CH2:37][CH2:36][CH2:35][C@H:31]3[C:32]([OH:34])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN5CCC[C@H]5C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), L-proline (28 mg) and acetic acid (0.1 mL) in DCM (10 mL) stirred at 20° C. was added sodium triacetoxyborohydride (52 mg). The reaction was stirred at 20° C. for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (25 mL) and aqueous HCl (2 M, 25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-L-proline (E69) (12 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.71 (1H, m), 1.94 (2H, m), 2.16 (1H, m), 2.95 (1H, m), 3.05 (2H, m), 3.25 (2H, m), 3.60 (2H, m), 3.65 (3H, s), 4.88 (1H, m), 7.20 (1H, t), 7.31 (1H, s), 7.45 (2H, m), 7.86 (1H, dd), 8.13 (1H, dd), 8.20 (1H, d). MS (ES): C27H29ClN4O4 requires 508; found 509.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[C@@H:20]([CH3:31])[CH2:19]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.Cl.CO>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH3:31])[CH2:19]3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Treat a solution of (S)-tert-butyl 4-(4-(4-fluorophenyl)phthalazin-1-yl)-2-methylpiperazine-1-carboxylate (7.05 g, 16.2 mmol) in 1,4-dioxane (50 mL) with 4 M HCl in 1,4-dioxane (25 mL). Add MeOH to dissolve the resultant precipitate and stir for 2 h at ambient temperature. Concentrate the reaction mixture under reduced pressure. Dissolve residue in MeOH and pour onto a 50 g Varian® SCX column. Rinse with MeOH and CH2Cl2, then elute the product with 1:1 CH2Cl2: 2 M ammonia in MeOH. Concentrate the eluent under reduced pressure to provide the title compound as a pale yellow foam (4.83 g, 93%). ES/MS m/z 323.2 (M+1).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][CH:5]1[O:11][C:12]([CH:14]1[CH2:18][C:17](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH2:16][N:15]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:13])([CH3:3])[CH3:2]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][CH:5]1[O:11][C:12]([CH:14]1[CH2:18][CH:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH2:16][N:15]1[C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])=[O:13])([CH3:3])[CH3:2]
Reactant: CC1CCC(C(C)C)C(OC(=O)C2CC(=Cc3cccc(F)c3)CN2C(=O)OC(C)(C)C)C1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1CCC(C(C)C)C(OC(=O)C2CC(Cc3cccc(F)c3)CN2C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
4-(3-Fluoro-benzylidene)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-(2-isopropyl-5-methyl-cyclohexyl)ester (1.20 g, 2.61 mmol) was dissolved in ethyl acetate:toluene (1:1, 12 ml). The solution was submitted to hydrogenation on platinum oxide (120 mg, 10% by weight) at 25° C. and 15 psi for 1 hour. The reaction mixture was filtered through arbocel and the filtrate reduced under pressure. The residue was purified by flashmaster chromatography eluting with heptane:ethyl actetate (15:1) to yield the title compound as a colourless oil (1.11 g, 91%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]2)[CH:3]=1.[NH2:28][C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:7]=[C:2]([NH:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[CH:3]=[C:4]([N:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:20][CH2:19]3)[N:5]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(N2CCN(S(C)(=O)=O)CC2)n1)c1ccc(Cl)cc1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCN(S(C)(=O)=O)CC2)n1)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.3 %

Procedure:
210 mg of (S)-6-chloro-N-[1-(4-chlorophenyl)ethyl]-4-[4-(methylsulfonyl)piperazin-1-yl]pyrimidine-2-amine, 56 mg of 2-aminopyrazine, 47 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 66 mg of sodium t-butoxide and 25 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 4 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 120 mg of (S)—N2-[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as pale yellow powder.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:7]2[N:13]=[CH:14][CH:15]=[CH:16][C:6]=2[CH2:5]1.C(OCC)C>C(O)(=O)C>[Br:1][C:15]1[CH:14]=[N:13][C:7]2[NH:8][CH2:9][CH2:10][C:11](=[O:12])[N:4]([CH3:3])[CH2:5][C:6]=2[CH:16]=1
Reactant: BrBr
Reactant: CN1Cc2cccnc2NCCC1=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN1Cc2cc(Br)cnc2NCCC1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Bromine (189 μL, 3.7 mmol) was added to a solution of 5-methyl-2,3,5,6-tetrahydropyrido[2,3-b][1,5]diazocin-4(1H)-one (460 mg, 2.4 mmol) in 10 mL of acetic acid and stirred at room temperature for 17 h. Add 30 mL of diethyl ether and collect orange solid product via suction filtration. Redissolve the solid in DCM and wash with NaHCO3, dry the organic layer over MgSO4, and concentrate in vacuo to obtain orange solid product. Yield 670 mg (quant); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=2.0 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 5.17 (bs, 1H), 4.49 (s, 2H), 3.59 (bm, 2H), 3.04 (t, J=6.8 Hz, 2H), 2.85 (s, 3H); ESI MS m/z 270, 272 [C10H12N3OBr+H]+
Reaction SMILES: ClC(Cl)C([O:5][N:6]=[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:8](Cl)=[O:9])=O.[NH2:17][C@@H:18]1[C:49](=[O:50])[N:20]2[C:21]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:22]([CH:25]([S:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)[CH3:26])[CH2:23][S:24][C@H:19]12.C1OC1C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:5][N:6]=[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:8]([NH:17][C@@H:18]1[C:49](=[O:50])[N:20]2[C:21]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:22]([CH:25]([S:27][C:28]3[NH:29][N:30]=[N:31][N:32]=3)[CH3:26])[CH2:23][S:24][C@H:19]12)=[O:9]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1
Agent: CC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NO)c3cccs3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
A solution of 2-dichloroacetoxyimino-2-(thien-2-yl)-acetyl chloride (syn-isomer) in dry methylene dichloride (6 ml of 15% solution, ca. 3 mmole.) was added, over 5 minutes, to a solution of diphenylmethyl 7β-amino-3-(1-methyltetrazol-5-ylthiomethyl)-ceph-3-em-4-carboxylate (1.24 g.) and propylene oxide (0.8 ml.) in methylene dichloride (20 ml.). After stirring for 30 minutes at 23°, aqueous sodium bicarbonate was added, and the two-phase mixture stirred for a further 30 minutes. The organic phase was separated, and washed with brine, and dried and evaporated to a foam (2.0 g.). A solution of this foam in benzene (20 ml.) was purified by chromatography on kieselgel with benzene: ethyl acetate (5:1) as eluent. Appropriate fractions were combined and evaporated in vacuo to give diphenylmethyl 7β-[2-hydroxyimino-2-(thien-2-yl)-acetamido]-3-(1-methyltetrazol-5-ylthiomethyl)-ceph-3-em-4-carboxylate as a foam (1.68 g.). A solution of this foam in trifluoroacetic acid (6 ml and anisole (1.5 ml) was kept at 23° for 5 minutes, and the solvents were removed at 40° (2 mm). The residue was dissolved in ethyl acetate (30 ml.), and the solution extracted with sodium bicarbonate solution. The alkaline extract was convered with ethyl acetate, and acidified to pH 2 with 2N-hydrochloric acid. The organic phase was separated, and washed with water, and brine, and the solvent evaporated in vacuo. The residue was dissolved in acetone, the solution treated with some charcoal and filtered through a pad of kieselguhr; the filtrate was dried and evaporated to a foam (1.085 g.). A solution of this foam in ethyl acetate was run into petroleum to give the title acid as a colourless, amorphous solid (852 mg, 71%), [α]D23 - 90° (C 0.91, acetone), λmax. (pH 6 phosphate buffer) 267.5 nm, (ε 18,000), νmax (Nujol) 3290 (NH), 1780 (β -lactam), 1720 (CO2H), and 1670 and 1530 cm.-1 (CONH), τ (DMSO-d6) values include 0.25 (NH, doublet, J 8 Hz.),. 4.14 (C-7 H, double doublet, J 4.5 and 8 Hz.), 4.79 (C-6 H, doublet, J 4.5 Hz), 6.05 (CH3).
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[I:8][C:7]1[C:2]([O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[S:9][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)=[CH:24][CH:23]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncccc1I
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Ic1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-3-iodopyridine (4.93 g, 22.11 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (6.16 g, 25.4 mmol), and cesium carbonate (10.81 g, 33.2 mmol) in DMSO (50 mL) was heated at 80° C. overnight. The reaction was cooled to rt and poured into water (200 mL). The solution was extracted with EtOAc (3×) and the combined organic layers were washed with brine, evaporated onto silica gel and purified by flash chromatography (Isco (240 gram)) eluting with EtOAc:hexanes (0:1→1:1) to give a white crystalline solid. MS (ESI, pos. ion) m/z: 445.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.C(=O)([O-])[O-].[K+].[K+].[K].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.O>C(#N)C>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:22]1[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]2[C:18]1=[O:28]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1c(Cl)cccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CC#N
Solvent: O
Product: Cc1c(Cl)cccc1CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
700 mg of 3-chloro-2-methylbenzyl chloride was dissolved in 10 mL of acetonitrile, and 829 mg of potassium carbonate and 889 mg of phthalimide potassium were added thereto at room temperature, followed by warming to 80° C., and then continuously reacting overnight. After completion of the reaction, the reaction liquid was left to be cooled, and water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.15 g (yield 100%) of a title compound as a white crystal.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].F[C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[CH:8]=[N:9][C:10]([CH3:17])=[N:11]2.C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[NH2:1][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[CH:8]=[N:9][C:10]([CH3:17])=[N:11]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ncc2c(F)ccc(F)c2n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc2c(N)ccc(F)c2n1
Yield: 22.6 %

Procedure:
The 3,6-difluoroanthranilic acid is heated in 8 ml of acetic acid anhydride for 45 minutes to 100° C. After cooling, the acetic acid that is produced and excess acetic acid anhydride are removed azeotropically with toluene in a vacuum. The residue is mixed with 40 ml of a 25% ammonia solution while being cooled with ice, and it is stirred for 72 hours. It is diluted with water and acidified with acetic acid. It is extracted with ethyl acetate, the organic phase is washed with water, dried on sodium sulfate and concentrated by evaporation. The thus obtained 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-3H-quinazolin-4-one and 6 g of phosphorus pentachloride are heated in 20 ml of phosphoryl chloride over 12 hours to 125° C. After cooling, it is poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried, and the solvent is removed. 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline, which is dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine, is obtained quantitatively. 600 mg of palladium on carbon is added, and it is shaken for 2 hours (480 ml of hydrogen absorption) under hydrogen atmosphere at normal pressure. Catalyst is removed from the solution by means of filtration on Celite, whereby it was rewashed with 100 ml of ethanol and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate-ethanol (0-40%), 550 mg of 5,8-difluoro-2-methylquinazoline is obtained. 890 mg (13.7 mmol) of sodium azide is added to 240 mg (1.3 mmol) of 5,8-difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of 18-crown-6 in 10 ml of DMF, and the mixture is heated for 8 hours to 125° C. The solvent is removed in a vacuum and chromatographed on silica gel with ethyl acetate, and 52 mg of product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])[S:5][CH:6]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1csc(C=O)c1
Product: Cc1csc(C=C[N+](=O)[O-])c1
Yield: 78 %

Procedure:
In close analogy to the procedure described above, 4-Methyl-thiophene-2-carbaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[C:11]([NH2:13])=[O:12].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>>[Cl:14][CH2:15][C:16]1[N:13]=[C:11]([C:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[O:12][CH:18]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C1=Cc2ccccc2CC1
Product: ClCc1coc(C2=Cc3ccccc3CC2)n1
Yield: 60 %

Procedure:
In substantially the same manner as in Reference Example 31, 3,4-dihydro-2-naphthalenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3,4-dihydro-2-naphthyl)oxazole. The yield was 60%. Recrystallization from isopropyl ether gave colorless prisms, mp 73-74° C.
Reaction SMILES: C[Al](C)C.[C:5](=[N:18][NH2:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:20]1(=[O:26])[O:25][CH:23]([CH3:24])[CH2:22][CH2:21]1.ClCCl.O>CCCCCCC.ClCCl>[C:6]1([C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:18][NH:19][C:20](=[O:26])[CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: CC1CCC(=O)O1
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: O
Product: CC(O)CCC(=O)NN=C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
At room temperature, 6.0 ml (12.0 mmol) of a 2.0 M trimethylaluminium solution in heptane are added dropwise to a solution of 0.78 g (4.0 mmol) of benzophenone hydrazone in 10 ml of dichloromethane, and the mixture is stirred for 30 min. A solution of 0.40 g (4.0 mmol) of γ-valerolactone in 5 ml of dichloromethane is then added dropwise to the reaction mixture. The reaction mixture is stirred at reflux for 2 h. A further 0.12 g (1.20 mmol) of γ-valerolactone is added, and the reaction mixture is stirred at reflux for 1 h. After cooling, dichloromethane/water is added to the reaction mixture. The organic phase is separated off and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 0.9 g (76%) of the desired product; (log P(HCOOH): 2.25); 1H-NMR (ppm): δ (DMSO-d6)=1.01 (d, 1H), 1.10 (d, 2H), 1.45-1.72 (m, 2H), 2.16-2.26 (m, 1H), 2.75-2.86 (m, 1H), 3.51-3.57 (m, 0.3H), 3.65-3.71 (m, 0.7H), 4.43 (d, 0.3H), 4.52 (d, 0.7H), 7.25-7.62 (m, 10H), 8.99 (s, 1H); LC-MS: m/z=297 [M+H]+
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][O:14][C@@H:15]2[O:20][C@@H:19]([CH2:21]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C@@H:15]2[O:20][C@@H:19]([CH2:21][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[CH2:18][CH2:17][CH2:16]2)=[CH:33][CH:34]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CO[C@H]2CCC[C@H](Cn3ccnc3)O2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A mixture of 0.28 g (12 mmoles) of 50% sodium hydride (i.e. 50% w/w sodium hydride in mineral oil) and 0.817 g (12 mmoles) of imidazole was stirred in 25 ml of dimethylformamide at 80° C. for 30 minutes. The mixture was then left to cool at room temperature, after which there was added a solution of 3.30 g of trans-6-(4-chlorobenzyloxy)-2-tosyloxymethyltetrahydropyran in 5 ml of dimethylformamide, at room temperature, and then the mixture was heated at 80°-85° C. for 2 hours. After cooling the mixture, it was poured into ice-water and then extracted with diethyl ether. The ethereal extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulphate, after which the solvent was evaporated off. The residue was purified by column chromatography through 50 g of silica gel eluted with a 30:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give 2.21 g of the title compound as a colourless oil.