Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([OH:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[O:29][CH2:2][C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)COc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
A mixture of 2-trimethylsilylethyl bromoacetate (J. Org. Chem. 51, 1537 (1986) (13.72 g, 56.0 mmol), 3-benzyloxy-4-nitrophenol (EP application 095121) (13.38 g, 55.9 mmol), and potassium carbonate (15.46 g, 112 mmol) in DMF (40 mL) is stirred at RT for 18 h. The mixture is poured into EtOAc and extracted once with water and five times with brine. The organic layer is dried, filtered, and concentrated to afford the title compound as a pale brown liquid: 1H NMR (CDCl3)δ 7.93 (d, J=9.1 Hz, 1H), 7.42 (d, J=7.1 Hz, 2H), 7.34 (t, J=7.1 Hz, 2H), 7.28 (t, J=7.1 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H), 6.41 (dd, J=9.1, 2.5 Hz, 1H), 5.15 (s, 2H), 4.57 (s, 2H), 4.25 (m, 2H), 0.97 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:56]=[CH:57][CH:58]=1)[O:5][C:6]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][C:42]=3[C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1)(=[O:13])=[O:12])=[O:9].[CH:59]1([CH:62]=O)[CH2:61][CH2:60]1.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:56]=[CH:57][CH:58]=1)[O:5][C:6]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][C:42]=3[C:49]3[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:62][CH:59]3[CH2:61][CH2:60]3)[CH2:23][CH2:22]2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1)(=[O:12])=[O:13])=[O:9]
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cccc(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: O=CC1CC1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCN(CC6CC6)CC5)c([N+](=O)[O-])c4)c(Oc4cccc(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A suspension of EXAMPLE 187B (50 mg), cyclopropanecarbaldehyde (100 mg) and MP-CNBH3 resin (0.2 g, 2.43 mmol/g) in dichloromethane (4 mL)/methanol (3 mL) was shaken for 16 hours at room temperature. The product was filtered, washed with dichloromethane/methanol and concentrated. The crude product was purified by RP HPLC(C8, 30%-100% CH3CN/water/0.1% TFA) to yield the product. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 8.35 (s, 1H), 8.10 (s, 1H), 7.67-7.75 (m, 1H), 7.60 (d, 1H), 7.36 (d, 2H), 7.15 (t, 1H), 7.07 (d, 3H), 6.89 (d, 1H), 6.73 (dd, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 6.40 (s, 1H), 3.86 (s, 1H), 3.12 (s, 5H), 2.71-2.80 (m, 3H), 2.13-2.28 (m, 9H), 1.98 (s, 3H), 1.79 (s, 1H), 1.41 (t, 2H), 0.99-1.11 (m, 2H), 0.94 (s, 6H), 0.84 (d, 1H), 0.63 (d, 2H), 0.33 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNc1ccccc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CN(c1ccccc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and N-methylaniline (20 μL, 0.301 mmol) by a procedure similar to example 1b and was isolated as white powder (40 mg, 80%). 1H NMR (CDCl3): 7.76 (dd, J=8.7, and 1.5 Hz, 1H), 7.56 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 7.46-7.35 (m, 3H), 7.24-7.20 (m, 2H), 6.98 (ddd, J=8.7, 6.6 and 1.5 Hz, 1H), 6.90 (dd, J=8.7 and 1.5 Hz, 1H), 3.65 (s, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1.Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][S:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:24])=[O:23])[C:16]=1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1>COCCOC>[Br:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][O:11][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][S:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:23])=[O:24])[C:16]=2[C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)CCc2ccccc2)cc1
Reactant: OCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCOc2ccc(Br)cc2)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
To a suspension of NaH (17 mg, 60% in mineral oil) in DME (5 ml) was added 2-(4-bromo-phenoxy)-ethanol (111 mg). The mixture was stirred at 50° C. for 1 h before 2-phenyl-ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (100 mg, Referential Example 1f) and K-tert.-butylate (25 mg) was added. The mixture was stirred at 70° C. for 16 h. A further portion of K-tert.-butylate (50 mg) was added and stirring was continued at 70° C. for 12 h and at rt for 72 h. The solvent was evaporated. The residue was treated with water (40 ml), acidified with 10% aq. citric acid and extracted twice with EA (50 ml). The organic phase was washed with water and evaporated. The crude product was crystallised from 2-propanol to give 2-phenyl-ethanesulfonic acid {6-[2-(4-bromo-phenoxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (127 mg) as a beige powder. LC-MS: tR=6.14 min, [M+1]+=568.38, [M−1]−=570.15.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCO)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 1.16 mL (10 mmol) of benzoylchloride in 10 mL dichloromethane is added to 0.93 mL (10 mmol) of 4-amino-butan-1-ol and 4.2 mL (30 mmol) of triethylamine dissolved in 50 mL of dichloromethane. The mixture is stirred overnight. 50 mL of saturated sodium carbonate solution is added. The organic phase is separated, dried with sodium sulfate and the solvent evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10]Br)[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([I:20])[CH:14]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][O:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][C:15]=2[I:20])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: N#Cc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1COc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 4-Bromo-2-bromomethyl-benzonitrile Example 347A (1.00 g, 3.64 mmol) and 4-Chloro-2-iodo-phenol Example 347B (0.94 g, 3.69 mmol) in dry DMF (8.0 mL) under argon was added 95% NaH (103 mg, 4.08 mmol). The reaction mixture was stirred at room temperature for 2.5 hours and quenched with water (30 mL). The resulting mixture was extracted with ether (180 mL). The organic layer was washed with water (1×30 mL), 1N NaOH solution (1×30 mL) and brine (1×30 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 614 mg of crude 4-Bromo-2-(4-chloro-2-iodo-phenoxymethyl)-benzonitrile Example 347C which was used as is for the next transformation.
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:5])[CH3:4].[F:7][C:8]1[CH:29]=[CH:28][C:11]([NH:12][C:13]2[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:10][CH:9]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[C:16]([C:15]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:13]([N:12]([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:29][CH:28]=2)[C:3](=[O:5])[CH3:4])[CH:14]=1)(=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1Nc1ccc(F)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(F)cc1)c1cc(C(=O)c2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
60% sodium hydride 79 mg and acetyl chloride 0.14 mL were added to N,N-dimethylformamide 5.0 mL solution of 3-(4-fluoroanilino)-4-methylbenzophenone 0.50 g under ice cooling sequentially, and it was stirred at room temperature for 4 hours. After the reaction mixture was cooled to ice temperature,60% sodium hydride 79 mg and acetyl chloride 0.14 mL were added sequentially, and it was stirred at room temperature for 5 hours and 30 minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=2:1] to give N-(5-benzoyl-2-methylphenyl)-N-(4-fluorophenyl)acetamide 82 mg of orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]#[C:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:9]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)o1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCCNC(=O)OC(C)(C)C)o1
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a solution of 5-(3-tert-butoxycarbonylamino-prop-1-ynyl)-furan-2-carboxylic acid methyl ester (1.69 g) in MeOH (50 mL) was added 10% palladium on carbon (850 mg) and the mixture was hydrogenated on a Parr shaker at 50 psi for 18 h. The catalyst was removed via filtration through Celite and the volatiles were concentrated in vacuo. Flash chromatography (hexanes:EtOAc 4:1) provided 5-(3-tert-butoxycarbonylamino-propyl)-furan-2-carboxylic acid methyl ester (422 mg, MS 284 M+) followed by 5-(3-tert-butoxycarbonylamino-propyl)-tetrahydrofuran-2-carboxylic acid methyl ester (903 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH2:11][CH2:12][CH3:13])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[CH2:25][CH2:26][CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH2:11][CH2:12][CH3:13])[C:9]=2[CH:10]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CCCn1ncc2c(C(=O)O)cc(Br)cc21
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2CCC
Yield: 42.4 %

Procedure:
The title compound was prepared in the same manner as described for example 42 (step b, part 2) from 6-bromo-1-propyl-1H-indazole-4-carboxylic acid (300 mg, 1.06 mmol) and 3-aminomethyl-6-methyl-4-propyl-1H-pyridin-2-one (190 mg, 1.06 mmol). The crude product was triturated with diethyl ether (10 mL) and n-pentane (10 mL) to afford the title compound as a white solid (200 mg, 42.5%). 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H), 0.90 (t, 3H), 1.48-1.46 (t, 2H), 1.86-1.80 (m, 2H), 2.13 (s, 3H), 2.50-2.32 (t, 2H), 4.40-4.35 (m, 4H), 5.90 (s, 1H), 7.69 (s, 1H), 8.20 (s, 1H), 8.35 (s, 1H), 8.62 (s, 1H), 11.52 (s, 1H). LCMS (ES+): m/z=445.17.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:37][O:38][CH2:39][C:40](O)=[O:41]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:40](=[O:41])[CH2:39][O:38][CH3:37])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COCC(=O)O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: COCC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and methoxyacetic acid (9.2 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[F:18][C:16]1[CH:15]=[CH:14][C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)=[O:11])[CH:17]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)nn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 464 (M+H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14](OB(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[N:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)Oc1ccncc1
Reactant: COC(=O)c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccncc2)s1
Yield: 54.2 %

Procedure:
To a solution of methyl 5-bromo-2-thiophenecarboxylate (884 mg), 4-pyridyl boric acid (500 mg), tetrakistriphenylphosphine palladium(0) (250 mg) in dimethoxyethane (15 ml) was added 2 M sodium carbonate solution (4 ml) and the solution was heated for 15 hours under reflux. The reaction solution was diluted with ethyl acetate and the organic layer was separated, washed with water and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with ethyl acetate. The extract was dried and concentrated to give pale yellow solid of methyl 5-(4-pyridyl)-2-thiophenecarboxylate (428 mg).
Reaction SMILES: [CH3:1][S:2][CH:3]1[N:6]([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC2C=CC=CC=2)[C:5](=[O:23])[CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[CH3:1][S:2]([CH:3]1[N:6]([CH2:7][C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:22])[C:5](=[O:23])[CH2:4]1)=[O:32]
Reactant: CSC1CC(=O)N1CC(=O)CCCCCCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)C1CC(=O)N1CC(=O)c1ccccc1
Yield: 80 %

Procedure:
Substituting 4-methylthio-1-phenacyl-azetidin-2-one (0.53 g, 2.25 mmol) for 4-methylthio-1-(9-phenyl-2-oxononyl)azetidin-2-one and using corresponding molar quantities of mCPBA as for Examples 5 and 6 gave 4-methylsulphinyl-1-phenacylazetidin-2-one (Example 8) as a waxy white solid (0.45 g, 80%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)O)[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.O>[N:21]([CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)[CH:3]([CH2:19][CH3:20])[CH2:1][CH3:2])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(CC)C(O)c1ncnn1Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)C(N=[N+]=[N-])c1ncnn1Cc1ccc(F)cc1
Yield: 67 %

Procedure:
To a stirred solution of 2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butan-1-ol (0.459 g, 1.42 mmol) in DMF (10 mL) was added sodium azide (0.277 g, 4.26 mmol) and the mixture was heated to reflux for 3 h. After cooling, the reaction mixture was diluted with H2O and extracted with EtOAc twice. The organic extracts were dried (MgSO4), filtered, concentrated in vacuo and purified by column chromatography (SiO2, EtOAc/hexane, 1:9) to yield a clear oil in 67% yield.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:12]3[O:13][C:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]=4[C:11]=3[CH:10]=[C:9](Br)[CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:28]1([S:34]([O-:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Na+]>>[N:1]1([CH2:6][C:7]2[C:12]3[O:13][C:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]=4[C:11]=3[CH:10]=[C:9]([S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])[CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cn4cccn4)cc(Br)cc3c2C1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cn4cccn4)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Yield: 39 %

Procedure:
The product of step B and sodium benzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash chromatography (SiO2, 80:20 hexanes/ethyl acetate) provided tert-butyl 6-((1H-pyrazol-1-yl)methyl)-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (18 mg, 39%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.05-7.96 (m, 1H), 7.95-7.85 (m, 2H), 7.62-7.40 (m, 6H), 6.32-6.25 (m, 1H), 5.60 (s, 2H), 4.56 (s, 2H), 3.83 (t, J=5.1 Hz, 2H), 2.95-2.80 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][N:12]=1.Br[C:20]1[N:24]2[CH:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:28][C:23]2=[N:22][CH:21]=1>>[F:17][C:16]1[C:11]([C:3]2[CH:4]=[C:5]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:30])[CH3:31])=[N:28][C:23]4=[N:22][CH:21]=3)[CH:6]=[CH:7][C:2]=2[F:1])=[N:12][CH:13]=[C:14]([F:18])[CH:15]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ncc(F)cc2F)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ncc(F)cc4F)c3)cnc2n1

Procedure:
4-Fluoro-3-(3,5-difluoropyridin-2-yl)phenylboronic acid was coupled with 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol by the method of Example 78. Purification by chromatography on silica gel eluting with dichloromethane containing 4% methanol and crystallisation from toluene/isohexane gave 2-[3-(3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol: δH (400 MHz, DMSO) 8.96 (1H, d, J 7), 8.72 (1H, d, J 2), 8.17 (1H, dd, J 2 and 1), 7.93 (1H, s), 7.85-7.91 (2H, m), 7.59 (1H, dd, J 10 and 8), 7.40 (1H, d, J 7), 5.51 (1H, s), 1.51 (6H, s); m/z (ES+) 385 (MH+).
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[H-].[Na+].[C:11]1([O:17][CH:18](Cl)Cl)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O.O>[O:17]([CH:18]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClC(Cl)Oc1ccccc1
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(Oc1ccccc1)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diethylphosphite (20.6 ml) was added dropwise at 20° C. to a stirred suspension of 55% sodium hydride (6.24 g) in dimethylformamide (90 ml). After stirring for a further 15 minutes, the mixture was cooled to 0° C., and dichloromethyl phenyl ether (9.27 g) was added dropwise. Stirring was continued overnight at 45° C., and the mixture was cooled in ice, diluted with water, neutralized and extracted with ethyl acetate. The organic phase was washed repeatedly with water, dried and evaporated in vacuo to yield an oil which was purified by chromatography on silica gel. Eluent: ether-acetone 85:15. The pure title compound was obtained as a colourless oil.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=1)[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[B:26](OC)([O:29][CH3:30])[O:27][CH3:28]>C1COCC1>[C:11]1([N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[CH:8]=[C:7]([B:26]3[O:29][CH2:30][CH2:28][O:27]3)[CH:25]=[CH:24][CH:23]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Brc1cccc(N(c2ccccc2)c2ccccc2)c1
Reactant: COB(OC)OC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: c1ccc(N(c2ccccc2)c2cccc(B3OCCO3)c2)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
First, 0.45 g of magnesium and 5 ml of THF were suspended, and a tiny amount of 1,2-dibromoethane was added to the obtained suspension. A mixed solution of 3.0 g of 3-bromo-N,N-diphenylaniline and 30 mL of THF was dripped to this suspension, and the mixture was stirred while being heated under reflux for 1.5 hours to cause a reaction. After the reaction, the solution which was naturally cooled to room temperature was cooled to −78° C., and 1.95 g of trimethyl borate was added thereto. The mixture was stirred while the temperature was increased to room temperature to cause a reaction. After the reaction, the solution was concentrated, and 4.8 mL of ethylene glycol and 30 mL of toluene were added to the obtained residue. The mixture was stirred while being heated under reflux for 12 hours to cause a reaction. After the reaction, the solution was filtered and the obtained filtrate was concentrated, so that a while solid was obtained (88% yield). The synthesis scheme of Step 1 is shown by (a-1).
Reaction SMILES: O.O.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+].[O:14]([C:16]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2=[N:25][CH2:26][CH2:27][N:17]12)O.CN(C)C=O>O>[C:16]([C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:18]1[NH:25][CH2:26][CH2:27][N:17]=1)(=[O:14])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OOC1(c2ccccc2)c2ccccc2C2=NCCN21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)c1ccccc1C1=NCCN1

Procedure:
A solution of 0.7 g. of sodium sulfite heptahydrate in 3 ml. of water was added to 0.5 g. of 2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole in 7 ml. of dimethylformamide. The solution was heated to 100° for 15 minutes. On cooling and addition of 20 ml. of water, 2-(2-benzoylphenyl)-2-imidazoline was obtained.
Reaction SMILES: [C:1]1([C:7]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23](=[O:29])[NH:24][CH2:25][CH2:26][O:27][NH2:28])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.CO>[C:1]1([C:7](=[N:28][O:27][CH2:26][CH2:25][NH:24][C:23](=[O:29])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])[C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=C(c1ccccc1)c1c[nH]c2cnccc12
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCON=C(c1ccccc1)c1c[nH]c2cnccc12
Yield: 89 %

Procedure:
tert-Butyl 2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methylene]amino]oxy]ethylcarbamate (429.2 mg, 89%) was prepared as a white foam using phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (Reference Example 8) and tert-butyl[2-(aminooxy)ethyl]carbamate following the procedure described for Example 104: Rf 0.42 (90:10 methylene chloride/methanol); 1H NMR (300 MHz, CD3OD) δ1.38-1.39 (9H, s), 3.40-3.44 (2H, m), 3.17-3.20 (1H, t, J=5.7 Hz), 3.26-3.28 (1H, t, J=5.3 Hz), 6.50-6.80 (1H, m), 7.30-7.50 (5H, m), 7.86-8.32 (2H, m), 8.76 (1H, s); ESI MS m/z 381 [C21H24N4O3+H]+; HPLC (Method A) 96.8% (AUC), tR=17.7 min.