Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=1)[NH:17][C:18]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:19]=1[C:20]([NH:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21]>>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[C:18]3[C:19](=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[C:20](=[O:21])[N:22]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:1]2=[O:2])[CH:37]=[CH:38][CH:39]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1cccc(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=c1c2cc(F)c(F)cc2n(-c2cccc(F)c2)c(=O)n1OCc1ccccc1
Yield: 31.2 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (4.7 g, 29 mmol) and crude 2-(3-fluoro-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example Z, 5.4 g, 14.5 mmol) provided 1.8 g of the title compound as a solid, mp 179-181° C.
Reaction SMILES: [CH3:1]N(C)C=O.[Br:6][C:7]1[CH:8]=[C:9]([OH:15])[C:10]([OH:14])=[CH:11][C:12]=1[F:13].C(=O)([O-])[O-].[Cs+].[Cs+].BrCCl>CCOCC>[Br:6][C:7]1[C:12]([F:13])=[CH:11][C:10]2[O:14][CH2:1][O:15][C:9]=2[CH:8]=1
Reactant: Oc1cc(F)c(Br)cc1O
Reactant: CN(C)C=O
Agent: ClCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: Fc1cc2c(cc1Br)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To N,N-dimethylformamide (25 mL) in a 50 mL flask was added 4-bromo-5-fluorobenzene-1,2-diol (2 g, 9.66 mmol), cesium carbonate (4.72 g, 14.49 mmol) and bromochloromethane (1.875 g, 14.49 mmol). The reaction mixture was allowed to stir at room temperature for 1 h and was then heated to an external temperature of 80° C. for 3 h. Upon cooling, the reaction mixture was diluted with Et2O (75 mL) and washed with water (50 mL) followed by a wash with saturated NaCl solution (50 mL). The organic layer was dried over MgSO4 and filtered. Concentration of the organic solution gave 5-bromo-6-fluorobenzo[d][1,3]dioxole as a light orange solid (1.8 g, 85%): 1H NMR (400 MHz, CDCl3) δ 6.94 (d, J=5.9 Hz, 1H), 6.67 (d, J=7.9 Hz, 1H), 6.00 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −113.82 (s); ESIMS m/z 220 ([M+H]+), 218 ([M−H]−).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=1)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[C:6]([C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH2:9][C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=1)#[CH:5]
Reactant: Cc1cc(C2=C(C#C[Si](C)(C)C)C(C)(C)CC(C)(C)C2)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#CC1=C(c2ccc(F)c(C)c2)CC(C)(C)CC1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To a solution of the product from Example 1, Step D above (5 g, 14.6 mmol), and acetic acid (1.3 ml, 21.9 mmol) in THF (15 ml) at 0° C. is added tetrabutylammonium fluoride in THF (1M, 21.9 ml, 21.9 mmol). The resulting solution is stirred for 12 hours at room temperature, diluted with ether and washed with saturated ammonium chloride solution. The ether fraction is dried over MgSO4, and the solvent is removed under reduced pressure. Purification by silica gel chromatography (100% hexane) provides 3.9 g (98%) of 1-(ethynyl)-2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexene: 1H NMR δ=1.0 (s,6), 1.22 (s,6), 1.45 (s,2), 2.15 (s,2), 2.25 (s,3), 2.75 (s,1), 6.95 (t,1), 7.15 (m,2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
A 2 L 24/40 three necked round-bottom flask equipped with a mechanical stirrer, a reflux condenser and a stopper, was charged with 15.427 g (72 mmol) of 4-methyl-2'-nitro[1,1'-biphenyl], 1.2 L of carbon tetrachloride, 14.164 g (80 mmol) of N-bromosuccinimide, and 0.50 g of 2,2'-azobis(2-methylpropionitrile). The stirred reaction mixture was refluxed under a nitrogen atmosphere for 4 hours, then cooled to room temperature and filtered. The filtrate was evaporated in vacuo and the residual oil was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate-hexane. Evaporation of the pure fractions afforded the product as a yellow crystalline solid (7.83 g, 37%) which had: mp 109°-110° C.
Reaction SMILES: C1(S(O[C@H:11]2[CH2:15][C@@H:14]([C:16](=[O:23])[NH:17][C:18]3([C:21]#[N:22])[CH2:20][CH2:19]3)[N:13]([C:24]([C:26]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:12]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[C:47]1([SH:53])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CC(N(C)C)=O.O>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2([C:24]([N:13]3[CH2:12][C@H:11]([S:53][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:15][C@H:14]3[C:16]([NH:17][C:18]3([C:21]#[N:22])[CH2:20][CH2:19]3)=[O:23])=[O:25])[CH2:28][CH2:27]2)=[CH:34][CH:33]=1
Reactant: Sc1ccccc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3ccccc3)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1
Temperature: 22 °C
Reaction time: 20 h
Yield: 101.5 %

Procedure:
To a suspension of (3S,5S)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-5-(1-cyanocyclopropylcarbamoyl)pyrrolidin-3-yl benzenesulfonate (example 457c; 200 mg) and potassium carbonate (134 mg) in dimethylacetamide (1 mL) was added at tetrahydrofuran (1.2 mL) at room temperature THF and benzenethiol (50.7 mg). The reaction mixture was stirred at 22° C. for 20 hr then poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless oil (184 mg; 89%). MS (ESI): m/z=466.13 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](I)[CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:22][CH2:23][CH3:24])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: CCCI
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Yield: 62.2 %

Procedure:
The reaction procedure of Example 11 was followed except that 939 mg (3.24 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 26 mg of lithium hydride and 551 mg of propyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 669 mg of 2-[(4-chlorophenyl)imino]-2,3-dihydro-3-propyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (62%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 112 mg of 2-[N-(4-chlorophenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (10%, recrystallized from ether) as a high polarity substance.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12](N(C)C3C=CC=CC=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:3])[CH3:2].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CCO>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:12]2[N:7]3[N:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[C:8]3[N:9]=[C:10]([S:21][CH3:22])[N:11]=2)=[CH:26][CH:25]=1
Reactant: NCc1ccc(Br)cc1
Reactant: CSc1nc(N(C)c2ccccc2)n2ncc(C(C)C)c2n1
Solvent: CCO
Product: CSc1nc(NCc2ccc(Br)cc2)n2ncc(C(C)C)c2n1
Yield: 75 %

Procedure:
According to the same conditions resulting in the preparation of the compound IIa.2, the compound IIb.4 is prepared from 8-isopropyl-4-(N-methyl-N-phenylamino)-2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazine and from 4-bromobenzylamine. Yield=75%. Mp=171-172° C. (EtOH). 1H NMR (300 MHz, CDCl3): δ 7.74 (s, 1H, Harom), 7.47 (d, 2H, J=8.3 Hz, Harom), 7.24 (d, 2H, J=8.3 Hz, Harom), 6.76 (bs, 1H, NH), 4.75 (d, 2H, J=6.0 Hz, CH2), 3.15 (hept, 1H, J=6.8 Hz, CH), 2.56 (s, 3H, CH3), 1.33 (d, 6H, J=6.8 Hz, 2 CH3). MS (ESI): m/z 394 (Br81, MH+), 392 (Br79, MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>C1COCC1>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]2=[O:9])=[CH:19][CH:18]=1
Reactant: COc1ccc[nH]c1=O
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccn(Cc2ccc(Br)cc2)c1=O
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a stirring reaction mixture of 3-methoxypyridine-2-one (2.00 g, 16 mmol) and K2CO3 (4.42 g, 32 mmol) in THF was added 4-bromobenzyl bromide (5.20 g, 20.8 mmol) slowly. Reaction mixture was the heated to reflux and stirring continued overnight. Reaction mixture was then cooled down and separated into organic and aqueous layer by adding CH2Cl2 (120 mL) and water (60 mL). Organic layer was separated and subsequently washed with water (2×60 mL), brine (1×40 mL). Organic layer was dried on Na2SO4 and solvent was evaporated in vacuo. Crude yellowish solid was triturated with hexanes to give pure white solid 145 (3.49 g, 74%) without further purification. 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 2H), 7.04 (m, 2H), 6.78 (dd, J=6.8, 1.2 Hz, 1H), 6.45 (dd, J=7.2, 1.6 Hz, 1H), 5.94 (t, J=7.2 Hz, 1H), 4.95 (s, 2H), 3.64 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.71, 149.91, 135.29, 131.49, 129.59, 127.53, 121.57, 111.82, 104.98, 55.54, 51.10. HRMS (EI) calcd for C13H12BrNO2 [M]+ 293.0051. found 293.0051.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]([O:33][CH2:34][C:35]#[CH:36])=[O:32]>>[CH2:34]([O:33][C:31](=[O:32])[N:14]([C@@H:13]1[C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][N:11]([C:16]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3([CH3:29])[CH2:28][CH2:27]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])[CH2:12]1)[CH3:15])[C:35]#[CH:36]
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: C#CCOC(=O)Cl
Product: C#CCOC(=O)N(C)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid prop-2-ynyl ester was prepared from rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using propargyl chloroformate instead of 4-fluorophenyl chloroformate and was obtained as a yellow foam. MS m/e: 552.3 [M]+.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:20]1([C:11]2[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]3[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=3[CH:10]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: [N-]=[N+]=NCC1Cc2cc(C3CCCC3)cc(-c3ccccc3)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NCC1Cc2cc(C3CCCC3)cc(-c3ccccc3)c2O1
Yield: 50 %

Procedure:
To a solution of 4-cyclopentylphenol (3.0 g, 18.0 mmol) in acetonitrile (30 mL) cooled to 0° C. was slowly added N-bromosuccinimide (3.29 g, 18 mmol) generally according to the procedure described for Example 309 afforded 3.75 g (84%) of 2-bromo-4-cyclopentylphenol Treatment of 2-bromo-4-cyclopentylphenol (3.75 g, 16.0 mmol) with potassium carbonate (5.4.0 g, 40 mmol) and allyl bromide (2.38 g, 20.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-cyclopentylphenol. Treatment of 2-allyl-6-bromo-4-cyclopentylphenol (3.0 g, 10.0 mmol) with 3-chloroperoxybenzoic acid (3.49 g, 12.0 mmol, 77%) followed by potassium carbonate (3.7 g, 25.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.68 g, (53%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.68 g, 4.6 mmol) with p-toluenesulfonyl chloride (0.96 g, 5.0 mmol) generally according to the procedure described for Intermediate 10 gave 1.78 g (70%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol) and 2-methylphenylboronic acid (0.45 g, 3.3 mmol) generally according to the procedure described for Intermediate 35 afforded 0.51 g, (99%) of (5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.239 g, 3.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (65%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.24 g, 0.48 mmol) according to the procedure described in Example 154 afforded 0.126 g (50%) of (±)-[(5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 190-193° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[OH:18])[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[OH:18])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(O)c(C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cc(C(=O)O)ccc1O
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a mixture of 1.00 g of the methyl 3-tert-butyloxycarbonyl-4-hydroxybenzoate and dioxane (10 ml) was added a 1 M aqueous sodium hydroxide solution (16 ml) at 25° C. and stirred overnight. The reaction solution was neutralized with 1 M hydrochloric acid, extracted with ethyl acetate, and dried over MgSO4. The solvent was evaporated under reduced pressure, thereby giving 0.78 g of 3-tert-butyloxycarbonyl-4-hydroxybenzoic acid.
Reaction SMILES: [NH2:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][C@:9]([C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:10])(=[O:4])=[O:3].Cl>CC#N>[NH2:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][C@@:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)([C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[OH:10])(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCNS(N)(=O)=O)c2cccc(Cl)c2)C1
Agent: Cl
Solvent: CC#N
Product: NS(=O)(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-tert-butyl 3-((S)-4-(aminosulfonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (0.0438 g, 0.095 mmol), CH3CN (35 mL) and 2 N aq HCl (30 mL) was vigorously stirred at rt for 24 h. The solvents were removed in vacuo to give the HCl salt of (S)-4-(aminosulfonylamino)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)butan-1-ol, which was used without further purification. LC-MS (3 min) tR=0.93 min, m/z 364, 362 (MH+), 285, 283.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:30][CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH:41]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:38]([CH3:40])[CH3:39])[O:33][CH2:32][CH2:31][CH2:30][N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([CH3:43])[CH3:42]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 33.1 %

Procedure:
To a suspension of NaH (60% in mineral oil, 121 mg, 3.02 mmol) in DMF (2.00 mL) was added Intermediate A (122 mg, 0.75 mmol) and the reaction stirred for 20 min. Intermediate 84f (317 mg, 0.75 mmol) was added in DMF (2.00 mL) and the reaction heated to 60° C. for 1 h. The cooled reaction was quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 2-10% [2M NH3 in MeOH] in DCM, gave the title compound (140 mg, 33%). LCMS (Method 4): Rt 2.37, m/z 564.2 [MH+].
Reaction SMILES: Cl.[NH:2]([C:6]1[S:7][C:8]([C:11](OCC)=[O:12])=[CH:9][N:10]=1)[C:3]([NH2:5])=[NH:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH:2]([C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: CCOC(=O)c1cnc(NC(=N)N)s1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: N=C(N)Nc1ncc(CO)s1
Temperature: 0 °C
Yield: 88.8 %

Procedure:
Ethyl 2-guanidino-5-thiazolecarboxylate hydrochloride (1.0 g; 3.99 mmoles) [prepared in Step A] was added to a cooled (ice-water bath) suspension of lithium aluminum hydride (0.46 g; 12.1 mmoles) in 25 ml of tetrahydrofuran. The reaction mixture was then heated at reflux temperature for 2 hours, cooled, decomposed with 0.46 ml H2O, 0.46 ml of 15% NaOH and 1.38 ml H2O and filtered. The filtrate was dried and evaporated under reduced pressure to give 0.61 g of product. Recrystallization from acetonitrile yielded the title compound, mp 168°-170°.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[C:8]([OH:10])=O.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[C:8]([Cl:13])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ncccn1
Temperature: 25 °C
Yield: 67 %

Procedure:
A stirred mixture of 0.837 g of 2-pyrimidinecarboxylic acid hydrochloride (prepared as described in S. Gronowitz et al. Ark. Chem, 1964, 22, 66-82), 30 mL of CHCl3 and 2 mL of thionyl chloride was heated at reflux for 12 h. After cooling to r.t., the suspension was filtered and the filtrate was evaporated to dryness in vacuo to afford 0.306 g (67%) of the title compound as a green solid used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1>C(OCC)(=O)C.CN(C=O)C>[NH2:18][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CN(c2ccc([N+](=O)[O-])cc2F)CCN1CCF
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(N2CCN(CCF)C(=O)C2)c(F)c1

Procedure:
3-Fluoro-4-(4-{2-fluoroethyl}-3-oxopiperazin-1-yl)nitrobenzene (4.35 g) is dissolved in a mixture of ethyl acetate (250 ml) and DMF (5 ml), and the solution flushed with argon. Palladium (10% on carbon, 200 mg) is added and the mixture hydrogenated under ambient pressure. After gas uptake had ceased, the mixture is filtered through celite and solvent removed. The residue is taken up in ethyl acetate, washed twice with water, dried over magnesium sulfate and the solvent is removed to give 5-amino-2-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]fluorobenzene which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16][C:17]1[C:24]([F:25])=[C:23]([C:26]([F:29])([F:28])[F:27])[C:22]([F:30])=[C:21]([F:31])[C:18]=1[CH2:19]Br>CN(C=O)C>[F:16][C:17]1[C:24]([F:25])=[C:23]([C:26]([F:29])([F:27])[F:28])[C:22]([F:30])=[C:21]([F:31])[C:18]=1[CH2:19][NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:13])([F:14])[F:15])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(OC(F)(F)F)c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1OC(F)(F)F
Yield: 80 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-trifluoromethoxybenzoic acid (1.35 g, 6.23 mmole), DMF (50 ml), TEA (6 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.10 ml, 6.73 mmole), 2.25 g (81.0% yield) of 5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid was obtained as a yellow solid.:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:5]2[C:10]([C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]>CO.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:3]=2[CH2:1][CH3:2])=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cn1c(CC)c(Cc2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cn1c(CC)c(Cc2ccc(N)cc2)c2ccccc21
Yield: 89.2 %

Procedure:
Into a dry reaction vessel, ethyl 2-[2-ethyl-3-(4-nitrobenzyl)-1H-indol-1-yl]acetate (350 mg, 0.96 mmol) was added, and dissolved in 10 mL methanol. 10% Pd/C 50 mg was added, purged with dry hydrogen, and reacted for 1 h. After completion of the reaction, it was filtered, and the filter cake was washed with methanol. The filtrate was rotate evaporated to dryness to obtain a white solid 288 mg, at a yield of 89.6%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)[CH2:37][C:33]2[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=2)=[CH:20][CH:21]=1)(=[O:14])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccnc1C=O
Reactant: CC(C)(C)OC(=O)NCCCCNS(=O)(=O)c1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC(=O)OC(C)(C)C)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.6 %

Procedure:
The compound (817.3 mg) obtained in Example 102-2 was dissolved in anhydrous methanol (24.5 ml) and added with 1-methyl-2-imidazolealdehyde (309.4 mg) and sodium cyanoborohydride (235.0 mg). Then, the solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 24 hours. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (910.0 mg) as a white solid.