Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:38]([O:42][C:43](Cl)=[O:44])[CH:39]([CH3:41])[CH3:40].CCOCC>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:43](=[O:44])[O:42][CH2:38][CH:39]([CH3:41])[CH3:40])[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)COC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
Dissolve the compound of Example 3 (120 mg, 0.23 mmol) in dichloromethane (3 mL) and add isobutylchloroformate (38 μL, 0.30 mmol) dropwise. After stirring for 10 minutes, pour the reaction into vigorously stirred ether (10 mL) and filter. Dissolve the solids in dichloromethane (10 mL) and wash with saturated aqueous sodium bicarbonate. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (4%) to give 104 mg of the title compound (73%): mass spectrum (ion spray): m/z=618.4 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:21].CCN(C(C)C)C(C)C.[CH2:32](Br)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][N:14]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:13]1)[CH2:11][C:10]2=[O:21]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Reactant: BrCCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)C1)O2
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A suspension of (E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (500 mg, 1.55 mmol, Intermediate 1) in DCM (15 ml) was treated with DIPEA (0.33 ml, 1.86 mmol) and phenethyl bromide (0.251 ml, 1.86 mmol), and stirred at RT for 8 days. The mixture was concentrated and the crude residue was purified by column chromatography (eluent: petroleum ether/EtOAc 7:3) to give (±)-(E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester a yellow solid (280 mg).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:12]=[CH:11][C:10]=1[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=O)(C)(C)C.[ClH:35]>O1CCOCC1.C(OCC)C>[ClH:35].[NH2:8][C:9]1[C:10]([C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])=[CH:11][CH:12]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(NC2CCCN(C(=O)OC(C)(C)C)C2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
670 mg (1.37 mmol) of tert-butyl 3-({6-[(tert-butoxycarbonyl)amino]-5-(trifluoroacetyl)pyridin-2-yl}amino)piperidine-1-carboxylate (Example 21A) were dissolved in 25 ml of a solution of hydrochloric acid in dioxane (4 M), and the mixture was stirred at RT for 20 h. After the reaction had gone to completion, the reaction mixture was diluted with diethyl ether (100 ml), and the precipitate was filtered off and washed with diethyl ether (100 ml) and dried. This gave 286 mg (64% of theory) of the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10](O)(=O)[CH:11]([CH3:13])[OH:12]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:10]([CH:11]([OH:12])[CH3:13])[O:9][C:3]=2[CH:4]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: CC(O)C(=O)O
Product: Cc1ccc2nc(C(C)O)oc2c1
Yield: 92 %

Procedure:
2-Amino-5-methylphenol as the starting material was reacted with lactic acid in the same manner as in Reference Example 1 (4) ii) to obtain 6-methyl-2-(1-hydroxyethyl)-benzoxazole (yield, 92%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)[C@@H](C1C=CC=CC=1)CN>O1CCCC1>[C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)[C@H](CN)c1ccccc1
Solvent: C1CCOC1
Product: C[C@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 10 °C
Yield: 45.9 %

Procedure:
(±)-2-(3-Benzoylphenyl)propionic acid (12.7 g, 50 mmol) was added to tetrahydrofuran (hereinafter abbreviated to "THF") (45 ml) and dissolved. Then, (S)-(+)-3-methyl-2-phenylbutylamine (4.1 g, 25 mmol) was added dropwise with stirring. After completing the addition, the reaction solution was maintained at 35° C. to 40° C. for one hour, stirred at room temperature for 4 hours, and then cooled to 10° C. The crystal precipitated was filtered, and the filter cake was washed with cold THF (35 ml) and then dried to give a diastereomer salt (5.84 g) of (S)-(+)-2-(3-benzoylphenyl)propionic acid with (S)-(+)-3-methyl-2-phenylbutylamine. The yield of the product based on (S)-(+)-2-(3-benzoylphenyl)propionic acid contained in the starting material was 56% and the optical purity was 94.3% e.e.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][O:14][NH:15][CH3:16].CC(C)N=C=NC(C)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]([O:14][CH3:13])[CH3:16])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 1000-mL round-bottom flask, was placed a solution of 4-bromo-2-fluorobenzoic acid (50 g, 229.36 mmol, 1.00 equiv) in dichloromethane (600 mL), N-methoxymethanamine hydrochloride (25 g, 257.73 mmol, 1.10 equiv). To the resulting mixture was added DIC (32 g, 253.97 mmol, 1.10 equiv) at 0° C. The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of water (500 mL). The solids were filtered out. The resulting solution was extracted with DCM (2×300 mL) and the organic layers combined. The resulting mixture was washed with water (2×300 mL), and sodium carbonate (1×300 mL). The resulting mixture was washed with brine (1×300 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum to yield 4-bromo-2-fluoro-N-methoxy-N-methylbenzamide as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([F:28])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([F:28])[CH:20]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH:7]=1
Reactant: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)cc1F
Reactant: OB(O)c1cncnc1
Product: COc1c(C)cc(C2(c3ccnc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1F
Yield: 11 %

Procedure:
The title compound was synthesized as described in Example 33 in 11% yield starting from 1-(2-bromopyridin-4-yl)-4-fluoro-1-(3-fluoro-4-methoxy-5-methylphenyl)-1H-isoindol-3-amine (330 mg, 0.74 mmol) and pyrimidin-5-ylboronic acid (101 mg, 0.82 mmol).
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1.[CH3:14][N:15](C=O)C>[Cl-].[NH4+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[F:13][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([NH:8][CH3:9])=[CH:7][C:2]=1[C:14]#[N:15]
Reactant: CN(C)C=O
Reactant: CNc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNc1cc(C#N)c(F)cc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A stirred solution of (5-Bromo-4-fluoro-2-nitro-phenyl)-methyl-amine (0.5 g, 0.0020 mol) in DMF (10 ml) was purged with Argon for 15 min. To the above mixture, Pd2(dba)3 (0.09 g, 0.001 mol), dppf (0.13 g, 0.0024 mol), and zinc cyanide (0.14 g, 0.0012 mol) was added carefully under argon atmosphere. The reaction mixture was heated at 120° C. for 22 h. Cooled to RT, diluted with saturated solution of ammonium chloride, filtered through CELITE® and the filter bed was thoroughly washed with ethyl acetate. The resulting mixture was separated, organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under vacuum to afford the crude compound, which was purified by column chromatography to obtain title compound 2-fluoro-5-methylamino-4-nitro-benzonitrile as a brick red solid. C8H6FN3O2; 1H NMR (400 MHz, CdCl3) δ 8.04 (d, J=9.2 Hz, 1H), 7.85 (brs, 1H), 7.11 (d, J=4.8 Hz, 1H), 3.05 (d, J=4.8 Hz, 3H). MS (M+1): 195.1.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[Na][S:17][C:18](=[C:21]([C:24]#[N:25])[C:22]#[N:23])[S:19][Na].O>CN(C)C=O>[N+:13]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]1[S:17][C:18](=[C:21]([C:24]#[N:25])[C:22]#[N:23])[S:19][C:11]1=[N:10]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Reactant: N#CC(C#N)=C(S[Na])S[Na]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)=C1Sc2nc3ccc([N+](=O)[O-])cc3nc2S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 2,3-dichloro-6-nitro-quinoxaline (0.5 g, 0.002 mol) in dimethylformamide (15 mL) is added, in several portions, di(sodiomercapto)methylenemalononitrile (0.53 g, 0.0029 mol). The resulting solution is stirred overnight at room temperature. Water (50 mL) is slowly added to the reaction mixture, dropwise, with stirring. The resulting solid is isolated by filtration, washed with water and dried, giving 0.48 g (78 percent yield) of a dark brown powder.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)=[C:2]=[O:3].[NH2:13][CH:14]([CH2:22][NH:23][C:24]1[C:29]([CH2:30][CH3:31])=[C:28]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:47]=[CH:46][C:45]4[CH2:44][CH2:43][CH2:42][NH:41][C:40]=4[N:39]=3)[CH2:34][CH2:33]2)[N:27]=[CH:26][N:25]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>O1CCCC1>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH:1][C:2](=[O:3])[NH:13][CH:14]([CH2:22][NH:23][C:24]3[C:29]([CH2:30][CH3:31])=[C:28]([N:32]4[CH2:33][CH2:34][CH:35]([C:38]5[CH:47]=[CH:46][C:45]6[CH2:44][CH2:43][CH2:42][NH:41][C:40]=6[N:39]=5)[CH2:36][CH2:37]4)[N:27]=[CH:26][N:25]=3)[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: C1CCOC1
Product: CCc1c(NCC(NC(=O)Nc2ccc3c(c2)OCO3)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
34 mg (0.207 mmoles) of 5-isocyanato-benzo[1,3]dioxole in solution in 3 ml of tetrahydrofuran is added to 120 mg (0.207 mmoles) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in solution in 5 ml of tetrahydrofuran. The reaction mixture is stirred at ambient temperature for 3 hours and 30 minutes. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silica gel with the following eluent: 100% ethyl acetate, ethyl acetate-dichloromethane/methanol (95/5) 50-50, ethyl acetate-dichloromethane/methanol (90-10) 50-50 and finishing with ethyl acetate/methanol (95-5). 60 mg of expected product is obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.[OH-].[Na+].Cl>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cccn2CCNC(C)=O)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCCn1cccc1-c1ccc(O)cc1
Temperature: -15 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
N-[2-[2-(p-Methoxyphenyl)pyrrol-1-yl]ethyl]acetamide (10.4 g) was dissolved in 300 ml of methylene chloride under argon, cooled to -15° C. and treated at this temperature while stirring with a solution of 11.6 ml of boron tribromide in 90 ml of methylene chloride. The mixture was stirred at -15° C. for 1 hour, at 0° C. for 2 hours and at room temperature overnight. The reaction mixture was treated at -10° C. with 270 ml of 2N sodium hydroxide solution and stirred at room temperature for 1 hour. 200 ml of methylene chloride were added to this mixture and the resulting mixture was adjusted to pH=8 with 70 ml of 2N hydrochloric acid. The phases were separated and the aqueous phase was extracted twice with 150 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 8.2 g of brown oil, was chromatographed on 250 g of silica gel with methylene chloride/methanol mixtures (50:1 to 20:1) as the eluent. There were obtained 5.4 g (55%) of N-[2 -[2-(p-hydroxyphenyl)pyrrol-1-yl]ethyl]acetamide as a colourless, amorphous solid which was processed without further purification. MS: (m/e)=244 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc(/C=C/C(=O)OC(C)(C)C)cn2)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(/C=C/C(=O)O)cn2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of tert-butyl ester 39 (0.45 g, 1.3 mmol) in DCM (5 mL) was added neat trifluoroacetic acid (1.7 mL). The reaction was allowed to stir at room temperature for 18 h then concentrated; the residue was triturated with diethyl ether, to give title compound 40 (0.376 g, 92% yield).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C@H:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:18]([O:20]C)=[O:19].[Li+].[OH-]>CO>[C:14]([O:13][C:11]([C@H:8]1[N:7]2[C:2](=[O:1])[C:3]([C:18]([OH:20])=[O:19])=[CH:4][N:5]=[C:6]2[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cnc2n(c1=O)[C@H](C(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(C(=O)O)c(=O)n21
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a solution of 1e (14.15 g, 48.1 mmol) in 250 mL MeOH at 0° C. was slowly added aqueous LiOH (1M, 48 mL, 48 mmol) over 15 min. The reaction was allowed to warm to rt overnight with stirring. The organic solvent was removed in vacuo. The residual aqueous solution was partitioned with Et2O, then the organic phase was extracted with H2O (2×). The combined aqueous extract was acidified to pH 2 with 1N HCl. The aqueous phase was extracted with CHCl3 (3×). The combined organic extract was dried (MgSO4) and concentrated to afford 11.4 g (85%) of the acid, if, as a tan crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[CH:10]1[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:17])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].[SH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:10]1[S:14](=[O:16])(=[O:15])[NH:13][C:12](=[O:17])[CH:11]=1)[CH2:8][S:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:33]=2)=[CH:28][CH:27]=1
Reactant: O=C1CC(c2ccc(CBr)cc2Br)S(=O)(=O)N1
Reactant: NS(=O)(=O)c1cccc(-c2ccc(CS)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cccc(-c2ccc(CSCc3ccc(C4=CC(=O)NS4(=O)=O)c(Br)c3)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
Into a 50 mL round bottom flask was placed benzyl bromide of Step 7 (17 mg, 0.045 mmol) and cesium carbonate (0.017 g, 0.054 mmol) under an atmosphere of nitrogen in anhydrous DMF (0.68 mL). The solution was cooled to 0° C., evacuated and refilled with nitrogen several times. 4′-(Mercaptomethyl)biphenyl-3-sulfonamide (15 mg, 0.054 mmol) in 2 mL anhydrous DMF was added to reaction solution dropwise. The resulting solution was stirred at 0° C. for 1 h. The crude material was purified by preparative LCMS to give product as a white solid (4.6 mg 17%). 1H NMR (400 MHz, CD3OD): δ 8.15 (m, 1H), 7.86 (m, 2H), 7.59 (m, 4H), 7.38 (m, 4H), 5.54 (dd, J=18.6, 6.8 Hz, 1H), 3.72 (s, 2H), 3.68 (s, 2H), 3.42 (m, 1H), 3.35 (m, 1H). LCMS found for C23H22BrN2O5S3 (M+H)+: m/z=581, 583.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]1[C:15](=O)[CH2:16][CH2:17][CH2:18][CH:19]=1)([CH3:3])[CH3:2]>C(N[Ti])CCC.C1(C)C=CC=CC=1>[CH2:5](/[N:13]=[C:15]1\[CH2:16][CH2:17][CH2:18][CH:19]=[C:14]\1[NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:1][CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1NC1=CCCCC1=O
Agent: CCCCN[Ti]
Solvent: Cc1ccccc1
Product: CCCC/N=C1\CCCC=C1Nc1c(C(C)C)cccc1C(C)C
Reaction time: 24 h
Yield: 104.6 %

Procedure:
The r indicates a number of repeat units of Ti(N(n-Bu)2. Reaction is set up in a glove box under N2 atmosphere. A 20-mL vial equipped with a stir bar is charged with (0.4858 g, 1.7900 mmol) of 2-(2,6-diisopropylphenylamino)cyclohex-2-enone (Preparation 3), toluene (6.0 mL) and (0.3022 g, 0.8984 mmol) of polymeric n-butylamino-titanium reagent (Preparation 4). The mixture is stirred overnight (24 hours). 1H-NMR of aliquot showed reaction is not complete. About 26% of starting material remained. Therefore, to the mixture are added 46.2 mg of polymeric n-butylamino-titanium reagent (Preparation 4). After stirring overnight, 1H-NMR of aliquot showed that no starting material remained. To the mixture are added hexanes, and the resulting mixture is filtered. Hexanes are also used to wash filtercake solids. The filtrate (yellow solution) is concentrated under reduced pressure to afford 305.8 mg (52.3%) of compound (B) of Example B as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@@H:13]([O:15][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)[CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CO[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
Sodium hydride (0.97 g, 24 mmol) was suspended in DMF (15 mL) under nitrogen at 0° C. A solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.0 g, 8.7 mmol) in DMF (20 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 10 min and treated with a solution of methyl 4-(bromomethyl)benzoate (2.3 g, 10 mmol) in DMF (5 mL). The reaction mixture was stirred at 0° C. for 1 h, and mixed with ethyl acetate and 1N HCl solution. The EtOAc layer was separated, washed with brine, and dried over MgSO4. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (1.2 g, 37%). 1H NMR (CDCl3) δ 7.99 (d, J=8.1 Hz, 2H), 7.36 (d, J=3.5 Hz, 2H), 4.78-4.26 (m, 3H), 4.19-4.11 (m, 1H), 3.90 (s, 3H), 3.71-3.46 (m, 2H), 2.84-2.39 (m, 1H), 2.23-2.04 (m, 1H), 1.48 (br. s., 9H); MS(ESI+) m/z 324.0 (M-55)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11](=[O:27])[N:12]([CH3:26])[C:13](=[O:25])[N:14]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:17])[CH:15]=1)(C(C)(C)C)(C)C.CC(O)=O.C1COCC1.O>O>[CH2:19]([NH:18][C:16]([N:14]1[CH:15]=[C:10]([CH2:9][OH:8])[C:11](=[O:27])[N:12]([CH3:26])[C:13]1=[O:25])=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCNC(=O)n1cc(CO[Si](C)(C)C(C)(C)C)c(=O)n(C)c1=O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCNC(=O)n1cc(CO)c(=O)n(C)c1=O
Reaction time: 22 h
Yield: 89.6 %

Procedure:
5-[[tert-Butyl(dimethyl)silyl]oxymethyl]-N-hexyl-3-methyl-2,4-dioxo-pyrimidine-1-carboxamide (0.05 g, 0.13 mmol) was treated with AcOH/THF/H2O (3 mL, 4:1:1) at room temperature. The reaction was stirred for 22 hrs. Water (3 mL) was added, and the solution extracted with EtOAc/cyclohexane 1:1 (3×6 mL). The combined organic phases were concentrated to approx. 1 mL, which was then diluted with dichloromethane (1.5 mL) and injected onto a 4 g SiO2 column followed by purification by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 70:30) to afford the title compound (0.033 g, 88%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J=6.8 Hz, 3H), 1.28-1.38 (m, 6H), 1.55-1.65 (m, 2H), 2.53 (bs, 1H), 3.38 (s, 3H), 3.39 (td, J=6.9, 5.8 Hz, 2H), 4.48 (s, 2H), 8.44 (bs, 1H), 9.26 (t, J=4.5 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 14.15, 22.66, 26.67, 28.06, 29.30, 31.53, 41.47, 59.62, 114.39, 133.97, 150.22, 152.31, 162.77. MS (ESI) m/z: 284 [M-H]+.
Reaction SMILES: [H-].[Na+].C(S)C.Cl.C[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:20][CH:19]2[CH2:18][NH:17][CH2:16]3)=[CH:11][CH:10]=1.CN(C)[CH:23]=[O:24]>>[CH:23]([N:17]1[CH2:18][CH:19]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)([CH2:20]2)[CH2:16]1)=[O:24]
Reactant: COc1ccc(C23CNCC2C3)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Product: O=CN1CC2CC2(c2ccc(O)cc2)C1

Procedure:
To a slurry of 7.2 g (0.15 mol) of sodium hydride (50% oil dispersion) in 170 ml of N,N-dimethylformamide at 0°-5° is added a solution of 10.1 ml of ethanethiol in 85 ml of N,N-dimethylformamide over a 15 minute period. An additional 3.16 g portion of sodium hydride is added followed gy 14.4 g of 1-(p-methoxyphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride. After the addition of 40 ml of N,N-dimethylformamide, the mixture is refluxed for 4 hours and the solvent is then removed. The residue is dissolved in 150 ml of water and mineral oil is extracted with ether. The aqueous solution is made acidic with acetic acid and the precipitated crystals are collected by filtration to give 9.8 g of 3-formyl-1-(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane as tan crystals, m.p. 166°-167°.