Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][OH:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][O:16][C:32](=[O:33])[NH:31][CH2:29][CH3:30])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CO)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNC(=O)OCc1c(C(=O)OCC)n(Cc2cccc3ccccc23)c2ccc(F)cc12
Reaction time: 16 h

Procedure:
To a solution 5-fluoro-3-hydroxymethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (51 mg, from Example 95) in dichloromethane (0.5 ml) was added 10 mg of ethyl isocyanate and stirring was continued at 22° C. for 16 h. 4-Dimethylaminopyridine (17 mg) was added and stirring was continued at 22° C. for 4 days. The mixture was chromatographed on silica using n-heptane/AcOEt (1:1) to give 3-ethylcarbamoyloxymethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless solid. MS: 471.3 ([M+Na]+). The product was dissolved in EtOH (1 ml), diluted with 1N aqueous NaOH (0.187 ml) and the mixture was heated to 45° C. for 1 h. The mixture was acidified with AcOH and purified by HPLC (RP-18, CH3CH/H2O, gradient) to give 3-ethoxymethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid as a white solid. MS: 376.5 ([M−H]−).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:35][C@@H:36]([CH2:49][NH2:50])[CH2:37][O:38][C:39]1[C:47]2[NH:46][C:45](=[O:48])[NH:44][C:43]=2[CH:42]=[CH:41][CH:40]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:29][CH2:30][CH:31]([NH:50][CH2:49][C@H:36]([OH:35])[CH2:37][O:38][C:39]5[C:47]6[NH:46][C:45](=[O:48])[NH:44][C:43]=6[CH:42]=[CH:41][CH:40]=5)[CH2:32][CH2:33]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Product: O=C1N=C(NC2CCN(Cc3ccccc3)CC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 21) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a pale yellowish solid; mp>165° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.9 Hz, 2 H), 2.55-2.95 (m, 6 H), 3.47 (s, 2 H), 3.75-4.05 (m, 5 H), 4.87 (brs, 1 H), 6.57 (d, J=7.5 Hz, 1 H), 6.61 (d, J=8.1 Hz, 1 H), 6.84 (t, J=8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.50 (m, 8 H), 9.46 (brs, 1 H), 10.57 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 341.6 ((M+2H)2+, 100%); 682.1 (MH+, 5%); HRMS Calcd. for C37H44N7O4S (MH+): 682.3176 Found: 682.3211.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:18][Si](C)(C)C)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[OH:18][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: COc1ccc(C(O[Si](C)(C)C)C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
30 g (0.091 mol) of 2-(4-methoxyphenyl)-1-phenyl-2-trimethylsilanyloxy-ethanone prepared in Step 2 was added to 50 mL of an aqueous 90% trifluoroacetic acid solution and the resulting reaction solution was stirred at room temperature for 2 hours. An ice bath was placed and the resulting reaction solution was neutralized with addition of sodium carbonate. Then, 200 mL of ethyl acetate and 100 mL of water were added to dilute the solution, followed by separation of layers. The obtained organic layer was washed twice with 100 mL of a saturated sodium bicarbonate solution and then successively washed twice with 100 mL of a brine solution. The organic layer thus obtained was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 17.25 g of a final product which was then recrystallized from ethyl acetate and hexane, to give 14.38 g (yield: 65%) of pure 2-hydroxy-2-(4-methoxyphenyl)-1-phenyl-ethanone.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7].C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[Cl:5][S:6]([N:9]1[C:2]([CH3:3])([CH3:1])[CH2:4][C:10]1=[O:11])(=[O:8])=[O:7]
Reactant: C=C(C)C
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC1(C)CC(=O)N1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a 3-neck 12 L flask equipped with an overhead stirrer, a 250 mL addition funnel topped with a nitrogen inlet and a rubber septum to allow a temperature probe and isobutylene needle was charged 450 mL of isobutylene. The flask was cooled in a dry ice-acetone bath. Ethyl ether (450 mL) was added and the resulting solution at -60° C. was treated with 210 mL (2.41 mol) of chlorosulfonyl isocyanate over 5 minutes at a rate so as to maintain the internal temperature below -50° C. The mixture was stirred at -50° C. to -62° C. for 30 minutes then allowed to warm slowly to room temperature and treated with 2250 mL of ether. The resulting solution was treated with 750 mL of 10% aqueous sodium carbonate slowly in 3 portions. The mixture was transferred into a 4 L separatory funnel and the aqueous layer removed. The organic layer was washed with 500 mL of water, then removed and treated with 750 mL of hexane. As crystallization began, additional hexane (250 mL) was added and the mixture concentrated under partial vacuum to a final volume of 3100 mL. The solid that formed was removed by filtration with the aid of 200 mL of hexane for rinsing. After air drying, the wet cake was dried under vacuum at 40° C. overnight to give 253 g (1.28 mol, 53%) of product as a pale yellow crystalline solid. Recycling of the mother liquors gave an additional 100 g (19%) of product as a white crystalline solid. 1H NMR (250 MHz, CDCl3): 1.89 (s,6H), 3.05 (s,2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12)[NH2:5].C(N(CC)CC)C.Cl[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a stirred solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (prepared in Example 1, Step B; 0.78 g, 3.0 mmol), triethylamine (0.84 mL, 6.0 mmol), and CH2Cl2 (5 mL) was added a solution of ethyl 2-chloro-2-oxoacetate (0.45 g, 3.3 mmol) in CH2Cl2 (1 mL) dropwise at room temperature. Stirring was continued for 15 minutes. The mixture was washed with water (3×5 mL), dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by Biotage Flash 40 silica gel chromatography, eluting with 30% EtOAc/hexanes, then 1:1 EtOAc/hexanes. The product was obtained as a white powder (656 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.53 (d, J=6 Hz, 1H), 7.85 (d, J=12 Hz, 1H), 7.76 (d, J=6 Hz, 1H), 7.58 (d, J=6 Hz, 1H), 7.39 (d, J=9 Hz, 1H), 7.30 (d, J=9 Hz, 1H), 6.52 (d, J=6 Hz, 1H), 4.44 (q, J=7 Hz, 2H), 1.44 (t, J=7 Hz, 3H). LRMS (APCI pos) m/e 361 (M+1). HPLC: 99% purity (220 nm).
Reaction SMILES: [OH:1][CH:2]([C:13]1[N:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)[CH2:3][N:4]1[CH:9]2[CH2:10][NH:11][CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2.[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@@H:32]1[CH2:34][O:33]1>>[OH:1][CH:2]([C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=1)[CH2:3][N:4]1[CH:9]2[CH2:10][N:11]([CH2:34][C@H:32]([OH:33])[C:23]3[C:22]([CH3:21])=[C:30]4[C:26](=[CH:25][CH:24]=3)[C:27](=[O:31])[O:28][CH2:29]4)[CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2
Reactant: N#Cc1ccc(C(O)CN2C3CNCC2COC3)nc1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Product: Cc1c([C@@H](O)CN2CC3COCC(C2)N3CC(O)c2ccc(C#N)cn2)ccc2c1COC2=O

Procedure:
6-(1-Hydroxy-2-(7-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)ethyl)nicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 18 starting from 6-[1-hydroxy-2-(3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)ethyl]pyridine-3-carbonitrile (INTERMEDIATE 18) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one [INTERMEDIATE 2].
Reaction SMILES: [S:1](=[O:5])(=O)(O)[OH:2].[NH2:6][C:7]1[NH:11][N:10]=[C:9](S)[N:8]=1.[Cl:13]Cl>Cl>[NH2:6][C:7]1[NH:11][N:10]=[C:9]([S:1]([Cl:13])(=[O:5])=[O:2])[N:8]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1nc(S)n[nH]1
Reactant: ClCl
Agent: Cl
Product: Nc1nc(S(=O)(=O)Cl)n[nH]1
Temperature: 18 °C

Procedure:
A 1 liter (L) bottom draining glass reactor was equipped with a fritted glass gas inlet tube, a gas outlet with a sulfuric acid scrubber, a paddle stirrer, a thermometer, and a jacket connected to a recirculating, temperature-regulated bath maintained at 18° C. A mixture containing 116 g (1.0 mole) of 5-amino-3-mercapto-1,2,4-triazole and 800 mL of 20 percent aqueous hydrochloric acid (made from 432 mL of 37 percent hydrochloric acid and 368 mL of water) was placed in the reactor and 222 g (3.13 moles) of chlorine was added through the gas inlet tube with stirring and cooling over a 165 min period. The temperature of the mixture was maintained at about 22° to about 32° C. under these conditions. The color of the mixture was changeable in the pale yellow to orange range and the initial slurry first thinned out and then became thick again as the reaction proceeded. After all the chlorine was added (uptake and the exotherm ceased), the temperature was reduced to about 5° C. and the mixture was removed through the bottom drain. The solids were collected by filtration, washed with 500 mL of cold water, and air dried to obtain 124 g (68 percent of theory) of the title compound as a pale yellow solid melting at 169.5°-170° C. (dec.). This material was analyzed to consist of 95.5 percent of the title compound and of about 4.5 percent of the corresponding sulfonic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH:10]([CH3:12])[CH3:11].O.NN.[OH-].[K+].O>C(O)COCCOCCO.C(OCC)(=O)C>[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)CC(=O)c1ccccc1N
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: OCCOCCOCCO
Product: CC(C)CCc1ccccc1N
Temperature: 210 °C
Yield: 72.1 %

Procedure:
A solution comprising 8.0 g (0.045 mol) of 1-(2-aminophenyl)-3-methylbutan-1-one (X-1), 6.8 g (0.135 mol) of hydrazine hydrate and 7.6 g (0.135 mol) of potassium hydroxide in 90 ml of triethylene glycol is heated at 210° C. for 6 h. For work-up, water and ethyl acetate are added at room temperature. The organic phase is again washed with water, dried over magnesium sulphate and concentrated under reduced pressure. Purification by column chromatography (cyclohexane/ethyl acetate 3:1) gives 5.3 g (71.5% of theory) of [2-(3-methylbutyl)-phenyl]amine.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Br:53][CH2:54][C:55](Br)=[O:56].C(N(CC)CC)C>C(Cl)Cl>[C:8]([O:27][CH2:28][CH2:29][N:30]([C:55](=[O:56])[CH2:54][Br:53])[CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Synthesis of (Z)-azanediylbis(ethane-2,1-diyl) dioleate TFA salt previously described. (Z)-azanediylbis(ethane-2,1-diyl) dioleate TFA salt (1.50 g, 2.34 mmol) was dissolved in DCM (20 mL) and placed in an ice-bath. Bromoacetyl bromide (214 uL, 2.46 mmol) was added followed by triethylamine (685 uL, 4.91 mmol). The ice-bath was removed and the reaction was allowed to stir overnight at room temperature under inert gas, then diluted with DCM to 100 mL, and washed with a 1M HCl (75 mL), H2O (75 mL), saturated NaHCO3 solution (75 mL) and saturated brine solution (75 mL). All aqueous washes were back extracted with DCM (25 mL). Dried organics with MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography with ethyl acetate yielded (Z)-((2-bromoacetyl)azanediyl)bis(ethane-2,1-diyl) dioleate (1.22 g).
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH2:5].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].[CH3:25][CH:26]([NH:28][CH2:29][CH2:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH3:27].[O-][Si]([O-])=O.[Mg+2]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:27][CH:26]([N:28]([CH2:29][CH2:30][S:31]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:32])=[O:33])[C:13]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:14])[CH3:25]
Reactant: CN(CCN)Cc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)NCCS(=O)(=O)c1ccccc1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)N(CCS(=O)(=O)c1ccccc1)C(=O)NCCN(C)Cc1ccccc1

Procedure:
A solution of 17.90 g (0.045 mole) of N-methyl-N-(phenylmethyl)-1,2-ethanediamine and 1,1'-carbonyldiimidazole (0.05 mole) in 100 ml of tetrahydrofuran was stirred at room temperature for 1 hour. To the mixture was added 10.52 g, (0.04 mole) of 1-methyl-N-[2-(phenysulfonyl)ethyl]ethanamine and the resulting solution heated overnight at gentle reflux. The reaction mixture was stripped to dryness and partitioned between chloroform and water; removal of chloroform gave a dark brown oil. The oil was dissolved in chloroform and extracted with 1N sulfuric acid (saturated with sodium chloride). The acidic layer was made alkaline, extracted with chloroform, and the solvent removed to give a light brown oil. The oil was subjected to chromatography on a Florisil column and eluted with methanol-methylene chloride. After combining appropriate fractions from the column and removing solvent, an oil was obtained. The oil was triturated with diethyl ether and dried at 80° C. in vacuo overnight. This furnished 6.75 g (40.4%) of clear oil.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:12]([OH:14])=[O:13])[C:5]([SH:11])([CH3:10])[CH:6]=[C:7]([CH3:9])[CH3:8])=[O:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH:1]([NH:3][CH:4]([C:12]([OH:14])=[O:13])[C:5]([SH:11])([CH3:10])[CH:6]=[C:7]([CH3:8])[CH3:9])=[O:2]
Reactant: CC(C)=CC(C)(S)[C@H](NC=O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)=CC(C)(S)C(NC=O)C(=O)O
Yield: 96.2 %

Procedure:
1.3 kilograms of N-formyl-isopropylidene-L-penicillamine were dissolved in 4.5 liters of toluene and treated with 30 ml. of acetic anhydride. This mixture was heated for 2 hours under reflux. After cooling to room temperature the pure N-formyl-isopropylidene-D,L-penicillamine crystallized out. There were obtained 1.25 kilograms of N-formyl-isopropylidene-D,L-penicillamine having a melting point of 140°-142°C. and [α]D20 = 0°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[C:15]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[C:17](Br)[N:16]=1.[CH3:24][N:25]([CH:27]=[O:28])C>CCCCCC>[C:24]1([NH:25][C:27]([C:15]2[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[C:17]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:16]=2)=[O:28])[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Reactant: CSc1cc(Br)nc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CSc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
2.06 g (0.0106×1.2 mol) of 3-(trifluoromethyl) phenol was dissolved in about 20 ml of DMF. The solution was further mixed with 0.45 g (ca. 60% in mineral oil; 0.0106×1.06 mol) of NaH and then with 3.00 g (0.0106 mol) of 2,6-dibromo-4-methylmercapto pyridine. After stirring at about 110° C. for about 2 hours, the mixture was allowed to stand for cooling to room temperature. After the reaction solution was distributed in hexane-saturated sodium bicarbonate water, the organic phase of the obtained solution was washed with saturated brine and dried with anhydrous sodium sulfate. The resultant solution was concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), and the obtained eluate was subjected to recrystallization using hexane, thereby obtaining an aimed product.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>CCO>[ClH:19].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: ClCc1cccc(Cl)c1
Solvent: CCO
Product: Cl
Product: Clc1cccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-chlorobenzyl chloride (0.199 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 196 mg of the product 203. 1H NMR (DMSO-d6) δ 11.37 (s, 2H), 7.85-7.45 (m, 4H), 7.20-6.90 (m, 6H), 6.90-6.60 (m, 4H), 5.78 (s, 2H), 4.93 (s, 2H); MS: m/z 379 (M++1).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Cl.CCN(C(C)C)C(C)C.[F:20][C:21]([F:44])([F:43])[C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:42])[C:30]2[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[C:33]([NH:39][CH3:40])=[CH:32][C:31]=2F)[CH2:24][CH2:23]1>O.CC#N>[F:20][C:21]([F:43])([F:44])[C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:42])[C:30]2[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[C:33]([NH:39][CH3:40])=[CH:32][C:31]=2[N:5]2[CH2:6][CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[CH2:4]2)[CH2:24][CH2:23]1
Reactant: FC(F)(F)C1CCNC1
Reactant: CNc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1cc(N2CCC(C(F)(F)F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 4.5 h

Procedure:
A mixture of 3-trifluoromethyl-pyrrolidine×HCl (53 mg, 0.30 mmol), DIPEA (0.40 ml, 2.4 mmol), N-(trans-4-trifluoromethyl-cyclohexyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (100 mg, 0.28 mmol) and MeCN (2 mL) is stirred for 4.5 h at reflux. Then the mixture is diluted with water and the formed precipitate is filtered, washed with water and dried
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12]OC(C)(C)C>C1(C)C=CC=CC=1.O>[Cl:12][C:5]1[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=[C:2]([CH3:1])[C:3]=1[NH2:4]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: CC(C)(C)OCl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])cc(Cl)c1N
Yield: 80.6 %

Procedure:
2-methyl-4-nitroaniline (56.0 g, 0.368 mol) was dispersed in toluene (430 ml) in a 1 liter four-neck flask. Tertiary butyl hypochloride (46.0 g, 0.423 mol) was added dropwise thereto, while cooled in iced water and stirred. The mixture was stirred at room temperature for 3 hours. The solids were filtered and washed three times with 200 ml of a 50% aqueous ethanol three times. They were then dried at 40° C. at a reduced pressure to obtain 55.33 g of a yellow solid (production yield 80%). The yellow solid was used in the subsequent step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13].[F-].[Cs+]>COCCOC.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])=[CH:16][CH:15]=1)#[N:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Cc1cc([N+](=O)[O-])ccc1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 125.7 %

Procedure:
A mixture of 2-bromo-5-nitrotoluene (7.05 gm, 32.67 mmol), 4-cyanophenylboronic acid (Tet. Lett., 1993, 34, 8237)(6.0 gm, 40.83 mmol), caesium fluoride (11.02 gm, 72.53 mmol) and tri-(2-methylphenyl)phosphine (1.0 gm, 3.27 mmol) in 1,2-dimethoxyethane (240 mL) were stirred under an atmosphere of nitrogen at room temperature for 40 mins. Tris(dibenzylideneacetone)dipalladiumn (1.50 gm, 1.63 mmol) was added and stirred for 10 mins at room temperature, then heated at 80° C. for 4 h. After being cooled, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated, washed with water, then dried (Na2SO4) and concentrated under reduced pressure to give crude 1-(4-cyanophenyl)-2-methyl-4-nitrobenzene (9.78 gm) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>C1COCC1>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][NH:37][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:3]=2)=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: NCc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
To a solution of tert-butyl 4-((6-chloro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (210 mg, 0.52 mmol), and Hunig's Base (0.18 mL, 1.04 mmol) in THF (3 mL) was added 4-(aminomethyl)phenol (96 mg, 0.78 mmol). The resulting mixture was refluxed for 1 hour. After cooling to rt, the solvent was removed and the crude product was purified by silica gel chromatography using 20-40% EtOAc/Hexanes to give tert-butyl 4-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (117 mg, 46%) as white solid.