Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[NH:3]1.C([Li])CCC.[Br:16][CH:17]([CH3:21])[C:18](Br)=[O:19].P([O-])([O-])([O-])=O>O1CCCC1.CCCCCC>[Br:16][CH:17]([CH3:21])[C:18]([N:3]1[C:2]([CH3:10])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5][C:4]1=[O:9])=[O:19]
Reactant: CC(Br)C(=O)Br
Reactant: CC1(C)NC(=O)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(Br)C(=O)N1C(=O)OC(C)(C)C1(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 4,4,5,5-tetramethyloxazolidin -2-one (0.30 g; 2.01 mmol) in tetrahydrofuran (2.5 ml), a hexane solution of 1.57 N n-butyl lithium (1.50 ml; 2.3 mmol) was added at 0° C., and after 5 minutes, 2-bromopropionyl bromide (0.54 g; 2.5 mmol) was added thereto and followed by stirring at the same temperature for 10 minutes. A phosphate buffer (pH 7) (1.1 ml) was added thereto to decompose the excess reaction agent, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate and then brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give a residue, which was purified by silica gel column chromatography (benzene→benzene:ethyl acetate=95:5) to give 3-(2'-bromopropionyl)-4,4,5,5-tetramethyloxazolidin-2-one as a colorless solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH:20]([CH3:22])[CH3:21])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH:20]([CH3:21])[CH3:22])[N:16]([CH3:1])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C1NS(=O)(=O)N(Cc2ccccc2)C1=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)C1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of potassium t-butoxide (3.53 g, 29 mmol) in THF was added a solution of 2-phenylmethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (7.7 g, 29 mmol) in THF at 0° C. and the mixture was stirred at this temperature for 1 hour. To the mixture was added methyl iodide (20.38 g, 0.143 mol) and the resulting mixture was allowed to stir at room temperature for 2.5 hours. The resulting mixture was quenched with brine, extracted with ether, and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 7.1 g (88%) of 2-phenylmethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =isopropyl; R3 =CH3) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[BH4-].[Na+].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26]>>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[N:13]1([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCNC1
Reactant: O=C1CCc2cccc(Cl)c2C1
Agent: O=C(O)/C=C\C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: Clc1cccc2c1CC(N1CCCNCC1)CC2

Procedure:
Employing the procedure of Example 3, 2.0 g (11.1 mmol) of 8-chloro-2-tetralone were reacted with 2.2 g (22.2 mmol) of homopiperazine, and the resulting product was reduced with sodium borohydride and the reduced product treated with maleic acid to obtain 0.13 g of the title compound as colorless crystals, m.p. 146°-148° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH2:26]>C(O)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][NH:26][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1
Reactant: NCc1c(F)cccc1F
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Product: O[C@H](CNCc1c(F)cccc1F)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole, 2,6-difluorobenzylamine, and ethanol essentially as described above in Example 112. Purity by LC/MS=96%, [M+H]+=429.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40]C)=[O:39])=[CH:32][CH:31]=4)([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:42])=[N:3]1.[OH-].[Na+].C(O)(=O)C>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:32][CH:31]=4)([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:42])=[N:3]1
Reactant: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4ccc(CCC(=O)O)cc4)c3)c2)n(C)n1
Yield: 70.8 %

Procedure:
A solution of Methyl 3-{4-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}propanoate (0.075 g, 0.129 mmol) in THF (3 mL) was cooled to 0° C. and slowly treated with 0.5M NaOH (1.29 mL, 0.643 mmol). The reaction mixture was allowed to slowly come to room temperature. Once the reaction was done by TLC, the reaction was acidified with acetic acid and then extracted with EtOAc (20 mL) and H2O (20 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered, and concentrated to give the title compound (0.052 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:20][C:15]4[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:13]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12Cc1ccccc1C2

Procedure:
A mixture of 6-bromo-indan-1-one (1.05 g, 5 mmol), 1,2-bis(bromomethyl)benzene (1.31 g, 5 mmol) in THF (50 mL) was added NaH (240 mg, 10 mmol) at room temperature, the mixture was refluxed for 2 hours. The mixture was quenched with water, concentrated, then extracted with DCM, washed with brine, dried over Na2SO4, concentrated to 6-bromo-1′,3′-dihydro-2,2′-spirobi[inden]-1(3H)-one (1.8 g, 33%).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br)[CH3:9].C([Li])CCC.CCCCCC.[CH3:31][C:32]([CH3:34])=[O:33]>>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[C:15]([C:32]([OH:33])([CH3:34])[CH3:31])[CH:14]=[CH:13][CH:12]=1)[CH3:9]
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1ccccc1Br
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN(CC=CC#CC(C)(C)C)Cc1cccc(C(C)(C)O)c1
Yield: 42.8 %

Procedure:
The procedure described in Example 17 was repeated, except that Compound 36 (2.35 g; 7.3 mmol), n-butyl lithium in n-hexane (1.56 M: 5.2 ml; 8.1 mmol), and acetone (1 ml) were used, to thereby yield 940 mg of the target compound (yield: 42.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]1[C:20]2[C:19](=[O:21])[NH:18][CH:17]=[CH:16][C:15]=2[NH:14][C:13]([CH3:22])=[C:12]1[N+:23]([O-:25])=[O:24])[C:6]#[N:7].F[B-](F)(F)F.[CH2:31]([O+](CC)CC)[CH3:32].ClCCl>CO>[CH2:31]([O:21][C:19]1[N:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:11]([C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([N+:23]([O-:25])=[O:24])=[C:13]([CH3:22])[NH:14]2)[CH3:32]
Reactant: COc1cc(C#N)ccc1C1C([N+](=O)[O-])=C(C)Nc2cc[nH]c(=O)c21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C([N+](=O)[O-])=C(C)N2

Procedure:
40 mg (0.11 mmol) of 3-methoxy-4-(2-methyl-3-nitro-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)benzonitrile and 43 mg of triethyloxonium tetrafluoroborate (0.23 mmol) are mixed under a dry argon atmosphere. After addition of dichloromethane (5 ml), the suspension is stirred until a solution is obtained, then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 13 mg (29% of theory) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[NH:17][CH2:18][CH2:19][N:20]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH:22]=1)#[N:2]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[NH:20][CH:19]=[CH:18][N:17]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH:22]=1)#[N:2]
Reactant: N#Cc1c(-c2ccnc(NC(=O)C3CC3)c2)sc(C2=NCCN2)c1-c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1c(-c2ccnc(NC(=O)C3CC3)c2)sc(-c2ncc[nH]2)c1-c1ccc(Cl)cc1Cl
Temperature: 120 °C
Yield: 41.6 %

Procedure:
A mixture of N-{4-[3-cyano-4-(2,4-dichlorophenyl)-5-(4,5-dihydro-1H-imidazol-2-yl)-2-thienyl]pyridin-2-yl}cyclopropanecarboxamide (0.0650 g, 0.135 mmol) and Magtrieve (0.143 g, 1.70 mmol) was taken up in toluene (5 mL) and heated at 120° C. for 4 hours. The mixture was cooled to room temperature, diluted with DCM (10 mL) and filtered through a pad of celite. The solid residue was washed with 1% ammonia, 9% methanol in DCM mixture (10 mL) and solvent from the filtrate was evaporated. The residue was purified using ISCO chromatography on silica gel, elution 10 to 70% ethyl acetate in hexanes to afford the product (0.027 g, 47%). LCMS: (FA) ES+, 480, 482. 1H NMR (400 MHz, d6-DMSO) δ: 11.88 (s, 1H) 11.11 (m, 1H), 8.57-8.55 (m, 1H), 8.53-8.50 (m, 1H), 7.85-7.84 (m, 1H), 7.58-7.56 (m, 2H), 7.54-7.52 (m, 1H), 7.17-7.16 (m, 1H), 7.00-6.98 (m, 1H), 2.08-2.00 (m, 1H), 0.87-0.81 (m, 4H).
Reaction SMILES: C(O[C:4](=[O:26])[CH2:5][O:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)C[CH2:9][CH2:8]1)C.[NH3:27]>>[C:20]1([S:17]([C:13]2[CH:14]=[C:15]3[C:16](=[CH:11][CH:12]=2)[CH:7]([O:6][CH2:5][C:4]([NH2:27])=[O:26])[CH2:8][CH2:9]3)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)COC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: N
Product: NC(=O)COC1CCc2cc(S(=O)(=O)c3ccccc3)ccc21

Procedure:
2-(5-Benzenesulfonyl-indan-1-yloxy)-acetamide was prepared from (6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yloxy)-acetic acid ethyl ester using the procedure of step 3 of Example 1, but replacing the methylamine hydrochloride with ammonia. MS: 332 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4C)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.[C:46]([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:23]([OH:24])[C@@:13]3([CH3:46])[OH:14])[C:6]=2[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1C(=O)O[C@H]1[C@@H](OC(=O)c2ccccc2)[C@H](n2c(=O)sc3cnc(N)nc32)O[C@@H]1COC(=O)c1ccccc1
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(=O)sc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a suspension of nucleoside 3 (380 mg, 0.606 mmol) in MeOH (20 mL) was added K2CO3 (17 mg, 0.12 mmol) at rt. The resulting mixture was stirred 18 h at rt whereupon it was treated with HOAc (15 μL, 0.25 mmol), concentrated and submitted to HPLC purification (MeCN—H2O), affording 20 mg (10%) of the title compound 4 as a white solid after lyophilization: 1H (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 6.86 (br s, 2H), 6.09 (br s, 1H), 5.19 (br s, 1H), 4.88 (br s, 1H), 4.55 (t, J=5.87, 1H), 3.97 (br s, 1H), 3.76-3.81 (m, 1H), 3.61 (br s, 2H), 1.04 (s, 3H); [M+H]+ m/z 315. Analysis calc'd for C11H14N4O5S.H2O: C, 39.75; H, 4.85; N, 16.86; S, 9.65. Found: C, 40.23; H, 4.76; N, 16.64; S, 9.45.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[CH2:15][C:16]1[S:20][C:19]([NH2:21])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:12][O:13][C:14](=[O:28])[CH2:15][C:16]1[S:20][C:19]([NH:21][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[OH:11])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)Cc1sc(N)nc1-c1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: COC(=O)Cc1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Yield: 32.1 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-acetic acid methyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23](OC(ON=C(C#N)C(OCC)=O)=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH2:23]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NOC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(CNC(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of N-benzyloxycarbonylglycine (0.42 g) and triethylamine (0.28 ml) in dioxane (5 ml), ethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate (0.55 g) is added, and the resulting mixture is stirred for 3 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine benzyl ester (0.57 g) as an oil.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[C:26]([F:39])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:40])[CH:10]=1)(=[O:5])=[O:4])[CH3:2].FC(F)(F)C(O)=[O:44]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CS(O)(=O)=O>[CH3:6][S:3]([OH:4])(=[O:5])=[O:44].[CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([F:39])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:40])[CH:10]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OC(C)(C)C)c(F)c3)c2)c(C)c1
Reactant: O=C(O)C(F)(F)F
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-{4-[({4′-[2-(ethylsulfonyl)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)amino]-2-fluorophenyl}propanoate (1.17 g, 2.05 mmol) in toluene (20 mL) was added trifluoroacetic acid (20 mL) under stirring at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-hexane/ethyl acetate=1/4) to give a colorless oil. The obtained oil was diluted with ethyl acetate, and methanesulfonic acid (0.12 mL) was added. The precipitated crystals were collected by filtration, washed and dried to give the title compound (1.00 g, yield 80%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:15][C:16]([O:18]C)=O)[NH:10][C:11]([NH:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].P([O-])([O-])([O-])=O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][C:16](=[O:18])[N:13]([CH3:14])[C:11](=[O:12])[NH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNC(=O)NN(CC(=O)OC)c1cccc(OC)c1
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(N2CC(=O)N(C)C(=O)N2)c1
Yield: 46.2 %

Procedure:
To a solution of methyl [1-(3-methoxyphenyl)-2-[(methylamino)carbonyl]hydrazino]acetate (1.6 g) in methanol (20 ml) under nitrogen was added a solution of sodium methoxide (8 ml; from sodium (5.2 g) in methanol (150 ml)). After 1 h the mixture was poured into pH 6 phosphate buffer (100 ml) and partitioned with dichloromethane (3×50 ml). The combined, dried organic extracts were evaporated to give a solid which was purified by FCC eluting with System A (7:3) to give, after trituration with System A (1:1), the title compound (650 mg), m.p. 120°-122°.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1.[C:17](#[N:19])[CH3:18]>>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][CH2:4][CH2:3][N:19]3[CH2:8][CH2:7][CH:6]([CH3:15])[CH2:18][CH2:17]3)=[CH:7][CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: ClCCNc1ccnc2cc(Cl)ccc12
Reactant: CC#N
Agent: Cl
Product: CC1CCN(CCNc2ccnc3cc(Cl)ccc23)CC1

Procedure:
2.72 g from 2.5 g of N-(2-chloroethyl)-7-chloro-4-quinolinamine hydrochloride; colourless crystals from acetonitrile, m.p.: 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C(=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)S(C)(=O)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(CO)c1
Yield: 38.7 %

Procedure:
On carrying out the operation according to the procedure of Example 58 starting with 5.1 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidine and 17 cm3 of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with a dichloromethane and ethanol mixture (97/3 by volume) as eluent and collecting 100 cm3 fractions. Fractions 10 to 14 are combined, concentrated to dryness under reduced pressure (2.7 kPa). The yellow solid obtained is taken up in 2 cm3 of dichloromethane and 10 cm3 of ethyl acetate and then filtered on sintered glass and washed with 2 cm3 of ethyl acetate. 1.6 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidine are obtained in the form of a white solid melting at 214° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (400 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.50 (2H, d, J=5 Hz, OCH2), 4.80 (1H, s, NCH), 5.25 (1H, t, J=5 Hz, OH), 7.30 (1H, d, J=7 Hz, CH arom.), between 7.35 and 7.45 (7H, m, 7CH arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.)].
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[CH:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NCc3ccccc3)nc2)c2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CNc2ccc(Cc3c[nH]c4ncccc34)cn2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
Into a round bottom flask was added compound 10 (400.0 mg, 0.85 mmol), tetrahydrofuran (20.0 mL) and tetra-n-butylammonium fluoride (240 mg, 0.93 mmol). The reaction mixture was stirred at 20 Celsius for 30 min. TLC indicated no starting material. The reaction mixture was poured into water, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage (methylene chloride/methanol 1:10) to give product 9 (Table 1 Cmpd 1-1) (220 mg, Yield=82.4%) as a white solid (M+1=315).
Reaction SMILES: ON1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2N=N1.C(N=C=NC(C)C)(C)C.C[N:21](C)[CH:22]=[O:23]>>[C:22]([NH2:21])(=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Agent: CC(C)N=C=NC(C)C
Product: NC(=O)c1ccccc1
Yield: 98 %

Procedure:
Rink amide resin (1.786 g; 1.00 mmol) is deprotected as described previously. The deprotected resin is shaken in a solution prepared from 4d (745 mg; 2.00 mmol), 1-hydroxybenzotriazole (810 mg, 6.00 mmol), N,N′-diisopropyl carbodiimide (1.010 g, 8.00 mmol) and dimethylformamide (100 mL) overnight at room temperature. The resin is washed thoroughly with several portions of dimethylformamide, then methanol, and finally dichloromethane. The washing continues until the latest filtrate is free of fluorescence. Solvents are evaporated under reduced pressure at room temperature. An aliquot of product (7a) is cleaved from the solid support (200 mg) by treatment of the resin with a 2:1 mixture of dichloromethane and triluoroacetic acid (10 mL) for 10 min. The solution is collected by vacuum filtration. The resin is further extracted with three portions of dichloromethane, followed by two portions of dimethylformamide. Removal of the solvents under reduced pressure and drying overnight in a desiccator provides 34.0 mg (98%) of 7a: mp 267-269° C.; homogeneous by thin layer chromatography: Rf=0.68; dichloromethane: methanol=9:1); 1H-NMR (DMSO-d6): 3.92 (s, 3H, OCH3); 7.43 (ddd, 1H); 7.61 (ddd, 1H); 7.95-8.00 (m, 3H); 8.13-8.16 (m, 4H); 8.23-8.25 (m, 3H); CONH2 broad (not assignable); 13C-NMR (DMSO-d6): 51.9 (COOCH3); 121.2; 121.6; 122.6; 123.0; 127.3; 127.9; 129.0; 129.4; 129.7; 132.5; 136.8; 139.9; 141.4; 144.4; 165.9 (CONH2); 167.03 (COOCH3).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClCCl
Product: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 114.1 %

Procedure:
To a suspension of 4-hydroxymethyl-1-tritylimidazole (6.13 g, 18 mmol) in dichloromethane (75 mL), cooled using an ice/water, was added dropwise thionyl chloride (5.0 g, 42 mmol) over 6 min. The ice/water bath was removed and the reaction was stirred for an additional 30 min. The DCM and SOCl2 were removed under reduced pressure. The resulting solid was triturated with diisopropyl ether (200 mL), collected by filtration and dried in vacuo to give 7.37 g (>100%) of 83% pure 4-(chloromethyl)-1-trityl-1H-imidazole; retention time, 7.33 min.; column: YMC ODS-A (3 μm, 50×4.6 mm); gradient: 10% to 100% B in A over 10 min. at 1.25 mL/min. Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in AcCN. LC/MS: ESI (M+H)+=359.2.