Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.N(CCO)[CH2:15][CH2:16][OH:17]>>[C:16]([O:13][C:1](=[O:12])[CH3:2])(=[O:17])[CH3:15].[C:6]1([C:4]2[O:13][C:1](=[O:12])[CH2:2][N:3]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: OCCNCCO
Product: CC(=O)OC(C)=O
Product: O=C1CN=C(c2ccccc2)O1

Procedure:
The methods of the invention are outlined in the following preparation scheme. All compounds were characterized by high-field NMR (1H, 13C, 11B) and by IR; new compounds were also characterized by combustion analysis (C,H,N). Bracketed numerals refer to like numbered reactions or reaction products in the drawing of the specification. In the first step 4-boronobenzaledhyde (2) was prepared in 93% yield from the ethylene glycol acetal of 4-bromobenzaldehyde (1) by a Grignard reaction with tributyl borate (10B enriched material may be used). The hydrolysis must be done at low temperature to produce (2) in high efficiency. Direct reaction of aldehyde (2) with uric or hippuric acid by the conventional procedure is not possible, as all attempts resulted in B-C cleavage. Therefore, the boronic acid group was protected by esterification with diethanolamine giving compound (3). Since the B-C cleavage described above probably resulted from reaction of the aryl boronic acid and ester with acetic anhydride, 2-phenyl-2-oxazolin-5-one was prepared and achieved the preparation of azlactone (4) in 62% yield by refluxing in dioxane. Boiling yellow (4) in 1% KOH.H2O for 15 min produced a colorless solution which, upon acidification, precipitated white N-benzoylamino-4-boronocinnamic acid (5) in 87% yield. The product was the desired Z isomer as evidenced by its vinyl resonance at δ7.44; the undesirable E isomer should resonate a δ6.66, by analogy with its un-boronated analogue, but no E isomer was observed.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(Cl)CCl.[Br:31][C:32]1[C:33]([CH2:49][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:36]([CH:40]=1)[C:37](O)=[O:38]>CN(C)C=O>[Br:31][C:32]1[C:33]([CH2:49][N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[C:36]([CH:40]=1)[C:37]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:38]
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1

Procedure:
Diisopropylethylamine (72.2 μl, 0.414 mmol), HOBT (38.0 mg, 0.248 mmol), 3-aminopyridine (29.2 mg, 0.310 mmol) and EDC (79 mg, 0.414 mmol) To a solution of 5-bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 7; 84 mg, 0.207 mmol) in N,N-dimethylformamide was added. The reaction was stirred over the weekend, then the solvent was removed in vacuo. Purification by MDAP gave the title compound as a white solid. 30 mg.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[C:16]=1[Cl:17]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2-c1ccccc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(-c3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 405 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][C:13]([OH:15])=O)=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:27]=1[CH2:28][NH2:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][C:13]([NH:29][CH2:28][C:27]3[C:30]([O:34][CH3:35])=[CH:31][CH:32]=[CH:33][C:26]=3[O:25][CH3:24])=[O:15])=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:6]=2[CH:23]=1
Reactant: COc1cccc(OC)c1CN
Reactant: Cc1ccccc1-c1c(CC(=O)O)c(=O)oc2ccc(Cl)cc12
Product: COc1cccc(OC)c1CNC(=O)Cc1c(-c2ccccc2C)c2cc(Cl)ccc2oc1=O

Procedure:
6-Chloro-4-(2-methylphenyl)-2-oxo-2H -1-benzopyran-3-acetic acid was reacted with 2,6-dimethoxybenzylamine by a method similar to Example 1(A) to yield the title compound.
Reaction SMILES: [BH4-].[Na+].[C:3]([C@H:8]1[S:12][CH2:11][C@H:10]([O:13][C:14](=[O:16])[CH3:15])[O:9]1)(OCC)=[O:4].CCOC(C)=O.CCCCCC>CO>[OH:4][CH2:3][C@H:8]1[S:12][CH2:11][C@H:10]([O:13][C:14](=[O:16])[CH3:15])[O:9]1
Reactant: CCOC(=O)[C@@H]1O[C@@H](OC(C)=O)CS1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CS[C@H](CO)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
Sodium borohydride (27 mg, 0.708 mmol) was added to a magnetically stirred solution of trans-2-carboethoxy-5-acetoxy-1,3-oxathiolane (52 mg, 0.236 mmol) in methanol (1 mL) at 0° C. under an argon atmosphere. The resultant solution was stirred for 25 minutes at 0° C. The reaction was quenched with 2 drops of saturated ammonium chloride solution followed by dilution with diethyl ether (4 mL). This mixture was stirred at room temperature for 15 minutes and then was dried over anhydrous magnesium sulphate. The drying agent was removed by suction filtration and the filtrate was concentrated under reduced pressure. The crude product obtained was subjected to column chromatography (50% EtOAc-hexane) to afford 21 mg (50%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([OH:14])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[OH:6].CO[C:18](OC)([CH3:20])[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]([C@H:4]1[C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[O:6][C:18]([CH3:20])([CH3:19])[O:14]1)=[O:15]
Reactant: COC(=O)[C@H](O)[C@@H](O)c1ccccc1Cl
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)[C@@H]1OC(C)(C)O[C@H]1c1ccccc1Cl
Temperature: 0 °C
Yield: 82.4 %

Procedure:
Dichloromethane(DMC) was added to (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate (24.4 g, Preparation example 25) and cooled to 0° C. 2,2-Dimethoxypropane (26 ml, 211.77 mmol) and p-toluenesulfonic acid (2 g, 10.58 mmol) was added and stirred at room temperature. The reaction mixture was quenched with H2O, extracted with DCM, washed with H2O, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (23.6 g, 70˜95%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:11])=[C:5]([C:7](F)(F)F)[N:6]=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](Cl)=[O:16].Cl>C1COCC1.N1C=CC=CC=1>[Br:11][C:4]1[S:3][C:2]([NH:1][C:15](=[O:16])[C:14]2[C:13]([F:12])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[N:6][C:5]=1[CH3:7]
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1Br
Temperature: 0 °C
Yield: 83 %

Procedure:
2-Amino-5-bromo-4-trifluoromethylthiazole (0.8 g) was dissolved in 3 mL of 1:1 mixture of THF and pyridine. 2,6-difluorobenzoylchloride (0.6 g) was added at room temperature with stirring. The mixture was stirred for 3 hours at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography on silica gel gave the title compound as a white solid. Yield 83%.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:40](=[O:41])[N:6]2[C:7]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[I:42][CH2:43][C:44]([NH2:46])=[O:45]>C(#N)C>[I-:42].[C:44]([CH2:43][N+:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]([C:16]2[N:17]=[CH:18][N:13]3[CH:12]=[C:11]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:40](=[O:41])[N:6]5[C:7]=4[C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=4)=[O:28])[S:15][C:14]=23)=[O:20])[CH:22]=1)(=[O:45])[NH2:46]
Reactant: NC(=O)CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5ccc[n+](CC(N)=O)c5)c4s3)[C@H](C)[C@H]12
Product: [I-]
Temperature: 50 °C
Reaction time: 6 h
Yield: 112.5 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (105.5 mg) was suspended in 2 ml of acetonitrile to prepare a suspension. 2-Iodoacetamide (340 mg) was added to the suspension, and the mixture was stirred at 50° C. for 6 hr. The reaction solution was concentrated under the reduced pressure, 5 ml of ethyl acetate was added to the concentrate, and the insolubles were collected by filtration to give 157 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo-[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate iodide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][C:15]=2[N:16]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][C:15]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3sc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2nc3cc(C4CCNCC4)ccc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]thiazol-5-yl}piperidine-1-carboxylate (130 mg, 0.27 mmol) dissolved in DCM (5 ml) and added TFA (0.5 ml). Reaction mixture stirred at rt for 3 h. DCM removed on rotavapour to obtain crude. Crude was triturated with ether to obtain 2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]thiazole 2,2,2-trifluoroacetate (150 mg). 2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]thiazole 2,2,2-trifluoroacetate (105 mg, 0.21 mmol) was dissolved in DCM (20 ml) and added TEA (0.23 ml, 1.66 mmol). This mixture stirred at rt for 30 mins and added isopropylchloro formate in toluene (51 mg, 0.42 mmol). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAc and Petether (1:3) as eluent to afford the titled compound (60 mg) as a grey solid. M.P.: 174-177° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.71-8.65 (m, 1H), 8.00 (d, J 1.2, 1H), 7.93-7.81 (m, 3H), 7.35 (dd, J 1.6, 8.4, 1H), 4.96 (septet, J 6.2, 1H), 4.40-4.22 (m, 2H), 3.12 (s, 3H), 2.95-2.82 (m, 3H), 2.0-1.90 (m, 2H), 1.80-1.64 (m, 2H), 1.28 (d, J 6.3, 6 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:15][N:14]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:13]2)[O:9][N:8]=1.O>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)[CH2:15][N:14]([C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[O:29])[CH2:13]2)[O:9][N:8]=1
Reactant: COCCO
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: O
Solvent: C1COCCO1
Product: COCCOc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 684 mg (8.99 mmol) of ethylene glycol monomethyl ether in 8.00 ml of 1,4-dioxane were added, at RT, 4 Å molecular sieve and 0.90 ml (0.90 mmol; 1 M solution in n-hexane) of phosphazene P4 base. Subsequently, 200 mg (0.450 mmol) of the oxadiazole from Example 23A in 2.0 ml of 1,4-dioxane were added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was admixed with water, filtered and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 89.8 mg (41% of theory).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][OH:7])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 75 %

Procedure:
Bis(2-hydroxyethyl)amine (5 g) was dissolved in N,N-dimethylformamide (100 ml), added with benzyl bromide (6.52 ml) and potassium carbonate (8.657 g) and stirred at room temperature for 21 hours. The reaction mixture was added with water (200 ml) and extracted twice with dichloromethane (200 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: dichloromethane:methanol=20:1→10:1) to obtain 7.631 g of the title compound. Yield: 75%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:16].[CH2:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])=[C:3]([F:16])[CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)c(F)c1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1F
Reaction time: 4 h
Yield: 31.8 %

Procedure:
5-(4-amino-3-fluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.31 g, 1.44 mmol) was dissolved in pyridine (3 mL), ethane sulfonyl chloride (0.12 mL, 1.3 mmol) was added, the mixture was stirred for 4 hours, and then water was added. The mixture diluted with ethyl acetate and the mixture was washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. Flash chromatography (5%-50% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-fluorophenyl]ethane sulfonamide (0.127 g). HPLC purity 100% at 210-370 nm, 8.3 min.; the Xterra™ RP18 instrument, 3.5/, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C14H14FN3O2S+H+, 308.08635; found (ESI, [M+H]+), 308.0855.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:15]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16].[CH3:29][I:30]>C(#N)C>[I-:30].[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][N:14]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[C:15]([N:17]1[CH:21]=[CH:20][N+:19]([CH3:29])=[CH:18]1)=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCN(C(=O)n1ccnc1)c1ccc(F)cc1
Reactant: CI
Solvent: CC#N
Product: C[n+]1ccn(C(=O)N(CCN2C(=O)c3ccccc3C2=O)c2ccc(F)cc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
To a 50 mL round-bottomed flask was added N-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-(4-fluorophenyl)-1H-imidazole-1-carboxamide (110 mg, 291 μmol, from step 2), acetonitrile (2 mL), methyl iodide (72.4 μl, 1163 μmol, Aldrich). The reaction mixture was stirred at RT for 24 h. The solvent was removed in vacuo to give the product (151 mg, 99.8% yield), which was used for the next step reaction without purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([C:11]2([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:19].C(N(CC)CC)C.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][C:41]1=[O:46]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]1([CH2:7][O:8][C:9]([C:11]2([NH:17][C:18]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][C:41]3=[O:46])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C1CCCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCCCN1C(=O)NC1(C(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A solution of 183 mg (1.5 mmol) of N,N-dimethylaminopyridine and 3.50 g (15 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in toluene was added to a solution of 3.27 g (15 mmol) of di-t-butyl dicarbonate in 60 ml of toluene, and the mixture was stirred at room temperature for 30 minutes. Thereafter, 3.04 g (30 mmol) of triethylamine, 1.83 g (15 mmol) of N,N-dimethylaminopyridine and 1.56 g (15.8 mmol) of 2-piperidone were added thereto, and the mixture was refluxed under heating overnight. Ethyl acetate was added to the reaction solution and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography to give 4.10 g (76%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14](=[CH2:18])[CH2:15][CH2:16]O)[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([I:19])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[N-:44]=[N+:45]=[N-:46].[Na+]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14](=[CH2:18])[CH2:15][CH2:16][N:44]=[N+:45]=[N-:46])[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([I:19])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C=C(CCO)CN(c1ccc(Cl)cc1I)S(C)(=O)=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=C(CCN=[N+]=[N-])CN(c1ccc(Cl)cc1I)S(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of N-(4-Chloro-2-iodo-phenyl)-N-(4-hydroxy-2-methylene-butyl)-methanesulfonamide obtained in Step A and triphenylphosphine (3.5 g) in dimethylacetamide (80 ml) at −10° C. under argon was added carbon tetrabromide (4.5 g). The reaction mixture was stirred at −10° C. for 45 min (a precipitate formed). Sodium azide (2 g) was added in one portion and the reaction mixture was stirred at 45° C. for 1 hour, cooled to room temperature, poured into water, extracted with ethyl acetate; the organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent cyclohexane:ethyl acetate 7:3) to afford N-(4-Chloro-2-iodo-phenyl)-N-(4-azido-2-methylene-butyl)-methanesulfonamide (1.96 g). 1H NMR (CDCl3, 400 MHz) 2.50 (m, 2H), 3.48 (m, 2H), 4.19 (d, J=12.0 Hz, 1H), 4.40 (d, J=12.0 Hz, 1H), 4.90 (s, 1H), 5.01 (s, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.36 (dd, J=0.9H, 8.5 Hz, 1H), 7.92 (d, J=0.9 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][Br:7].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:26][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([NH:13][C:12]3[CH:27]=[CH:28][C:9]([Cl:8])=[CH:10][C:11]=3[F:29])=[N:15][CH:16]=[N:17]2)=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOCCBr
Yield: 52.3 %

Procedure:
2-Bromoethyl ether (1.57 ml, 12 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1 g, 3.1 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (1.73 g, 12 mmol) in DMF (10 ml). The mixture was s for 18 hours at ambient temperature and was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/acetonitrile/methanol (60/38/2). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (763 mg, 52%).
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([OH:23])C>>[OH:23][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]=[CH:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:2]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: CCO
Product: Oc1ccccc1N=Cc1cccc2ccccc12
Temperature: 70 °C

Procedure:
6.88 g (40.0 mmol) of 2-hydroxy-1-naphthaldehyde was dissolved in 10 ml ethanol under heating, and 3.72 g (40.00 mmol) of aniline was added. After stirring under reflux at 70° C. for 1 hour, completion of the reaction was confirmed by TLC. Upon being left at rest over night in the refrigerator, a crystal was formed, and the resulting precipitation was filtered by Kiriyama funnel. Drying under reduced pressure at 25° C. for 24 hours gave 2-hydroxy-1-naphthylmethylidene aniline (hereinafter, also referred to as “HNA”) as a yellow crystal (9.17 g, 93%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH2:26][CH2:27][O:28][CH2:29][C:30]#[C:31][CH2:32][CH2:33]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH2:33][CH2:32][C:31]#[C:30][CH2:29][O:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCC#CCOCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCC#CCOCCc1ccccc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A solution of triphenylphosphine (5.25 g) in dry DCM (15 ml) was added to a solution of the product of step (ii) (3.9 g) and carbon tetrabromide (6.63 g) in dry DCM (25 ml) at 0° over 10 min. The yellow solution was stirred at 0° for 30 min, evaporated onto silica (Merck 9385) and purified by FCC eluting with H→H-ER (3:1) to give the title compound as a colourless oil (2.7 g). T.l.c. (H-ER 2:1) Rf 0.69.