Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Br:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1>>[S:1]([O:14][CH2:13][CH2:12][O:11][C:10]1[CH:15]=[CH:16][C:7]([Br:6])=[CH:8][CH:9]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: OCCOc1ccc(Br)cc1
Reactant: NS(=O)(=O)Cl
Product: NS(=O)(=O)OCCOc1ccc(Br)cc1
Yield: 69 %

Procedure:
The title compound was prepared by the procedures of Example 33 from sulfamoyl chloride and 2-(4-bromophenoxy)ethanol as white solid, mp 134°-137° C., in 69% yield.
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:25]([OH:27])=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH2:35]([N-:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(NCC)C>ClCCl>[NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:25]([OH:27])=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:35]([N-:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCCCCCCCCCCCCC[N-]CCCCCCCCCCCC
Solvent: CCNCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reaction time: 5 h
Yield: 56.2 %

Procedure:
1.377 g Boc-Lys(Fmoc)-N-lauryl-N-myristyl-amide were dissolved in 16 ml anhydrous dichloromethane in a 50 ml round-bottom flask. 6 ml diethylamine were added and the mixture was steered at room temperature for 5 hours (FIG. 8). The volatile components were removed using a rotary evaporator and the residue was purified by chromatography using 40 g silica gel 60 (Merck) with hexane/ethylacetate 5:1. The product was eluted using a step gradient consisting of ethylacetate, dichloromethane and dichloromethane/methanol 3:1. 556 mg (0.911 mmol) Boc-Lys-N-lauryl-N-myristyl amide were obtained as yellowish viscous oil as well as 119 mg of a mixed fraction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:15][CH2:14][CH2:13]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].CO>O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[CH2:13][CH2:14][CH2:15]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C2CCC2)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(C(=O)O)ccc1C1CCC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
Into around-bottom flask, was placed a solution of methyl 3-amino-4-cyclobutylbenzoate (1.00 g, 4.87 mmol, 1.00 equiv) and sodium hydroxide (compound 443.2, 800 mg, 20.0 mmol, 4.00 equiv) in a solvent mixture of methanol and H2O (20/10 mL). The resulting solution was stirred for 8 h at 20° C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The pH of the remaining aqueous layer was adjusted to ˜4-5 with HCl (aqueous, 1 M). The resulting precipitate was then collected by filtration and dried to furnish 500 mg (54%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCO.O=[Pt]=O>[CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cc(Cc2ccccc2)ccn1)C(=O)OCC
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CC1CC(Cc2ccccc2)CCN1)C(=O)OCC
Reaction time: 16 h
Yield: 113.6 %

Procedure:
To a solution of diethyl 2-((4-benzylpyridin-2-yl)methyl)malonate (2.6 g, 7.6 mmol) in EtOH (30 mL) were added PtO2 (70 mg) and conc. HCl (0.7 mL). The heterogeneous mixture was hydrogenated in a Parr hydrogenator at 30-35 psi at 25° C. for 16 h. The reaction was filtered through a Celite pad and was concentrated under reduced pressure to give the crude title compound as a yellow oil (3.0 g, 100%): 1H NMR (CDCl3) δ1.10-1.30 (m, 6H), 1.50-2.00 (m, 6H), 2.20-2.35 (m, 1H), 2.50-2.65 (m, 2H), 2.65-2.85 (m, 1H), 3.00-3.15 (m, 1H), 3.55-3.70 (m, JH), 3.90-4.05 (m, 1H), 4.05-4.30 (m, 4H), 7.08-7.32 (m, SH), 9.70 (bs, 2H) ; IR (film) 2927, 1735 cm−1.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=O)[C:13]([Cl:19])=[C:14]([Cl:18])[C:15]([OH:17])=[O:16])=[C:4]1[CH3:21])[CH3:2].[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([C:31]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]=3[CH3:22])[O:17][C:15](=[O:16])[C:14]([Cl:18])=[C:13]2[Cl:19])=[C:4]1[CH3:21])[CH3:2]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CCn1c(C)c(C(=O)C(Cl)=C(Cl)C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3c(C)[nH]c4ccccc34)OC(=O)C(Cl)=C2Cl)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (0.047 mole) of 4-(1-ethyl-2-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid, 4.0 g (0.030 mole) of 2-methylindole and 150 ml of acetic anhydride was stirred at ambient temperature in an atmosphere of air for approximately seventeen hours and the solid which formed was collected by filtration. After drying in vacuo at 60° C. there was obtained 5-(1-ethyl-2-methyl-3-indolyl)-5-(2-methyl-3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula V: R=CH3CH2 ; R1 =R3 =CH3 ; R2 =Y=Y1 =H) as a blue-colored solid which melted over the range of 282°-285° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18](OCC)(=[O:23])[CH2:19][C:20]([CH3:22])=O>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:23])[CH:19]=[C:20]([CH3:22])[NH:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(=O)n(-c2ccc(F)cc2)[nH]1
Reaction time: 4 h
Yield: 89 %

Procedure:
(4-Fluorophenyl)hydrazine hydrochloride (20.0 g, 0.123 mol) was added to a solution of triethylamine (20.5 mL) in methanol (350 mL). Then, a solution of ethyl acetoacetate (16.0 g, 0.123 mol) in methanol (50 mL) was added. The resulting reaction mixture was stirred for 4 hours under reflux and extracted with dichloromethane and sodium chloride aqueous solution. The aqueous layer was extracted again with dichloromethane. All the organic layers were collected, dried with Na2SO4 and then filtered. The filtrate was concentrated. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2). The target compound was yielded (21.0 g, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:37][C:36]([F:39])([F:38])[CH2:35]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:37][C:36]([F:39])([F:38])[CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S(=O)(OCC1CC(F)(F)C1)C(F)(F)F
Product: COc1cn(C(CC2CC(F)(F)C2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
600 mg (1.60 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.92 ml (1.92 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 1162 mg (purity 70%, 3.20 mmol, 2.0 eq.) of (3,3-difluorocyclobutyl)methyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 417 mg (52% of theory)
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:48][C@H:49]2[O:51][CH2:50]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1>CN(C=O)C>[CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:48][C@@H:49]3[CH2:50][O:51]3)=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CCCCc1nc(-c2ccc(O)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol (0.42 g, 1.0 mmol, 1.0 eq.) and Cs2CO3 (1.0 g, 3.0 mmol, 3.0 eq.) in DMF (3 mL) was stirred and preheated to 80° C. The reaction mixture was then treated with a solution of (2S)-(+)-glycidyl tosylate (0.27 g, 1.2 mmol, 1.2 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C. for ˜30-60 min following completion of the addition. Analysis of the reaction by TLC and LC/MS showed that the starting phenol had been consumed and the desired alkylated-phenol was the major product. The reaction was then cooled and diluted with EtOAc and washed with brine. The organic phase was dried with Na2SO4 and evaporated in vacuo. The crude alkylated-phenol was then purified by flash column chromatography over silica gel (EtOAc/hexanes ˜1:3).
Reaction SMILES: Cl.[F:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:15]1[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:12]([O:11][C:9]([C:3]1([F:2])[CH2:4][CH2:5][N:6]([C:15]2[N:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][N:16]=2)[CH2:7][CH2:8]1)=[O:10])[CH3:13]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: CCOC(=O)C1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(F)CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.2 %

Procedure:
A mixture of ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (2 g, 9.4491 mmol), (2-chloropyrimidin-5-yl)boronic acid (1.5426 g, 9.4493 mmol) and sodium carbonate decahydrate (2.53 g, 23.6 mmol) in ethanol (15 mL) was stirred at 60° C. for 12 h. The reaction mixture was filtered through celite, the solvent was evaporated and the residue was dried under vacuum to give the title compound (2.7 g, 97%) as a pale yellow gum, which was used without further purification. LCMS (pH 10) MH+ 298, RT 1.19 minutes.
Reaction SMILES: [OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[I-].[I-].[Na+].[S:42]1[CH:46]=[CH:45][N:44]=[CH:43]1>CN(C=O)C.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][C:43]2[S:42][CH:46]=[CH:45][N:44]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: c1cscn1
Reactant: CCCOc1c(OCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCOc1c(OCCc2nccs2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O

Procedure:
trans-2-[3-(2-Hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(2-bromoethoxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (50 mg, 0.08 mmol) (Example 12) was converted into the corresponding iodide by treatment with sodium iodide in DMF. The iodo intermediate and thiazole (0.17 mL, 2.4 mmol) in toluene (5 mL) was heated under reflux overnight. The solution was evaporated to dryness, and the product was isolated by preparative TLC (chloroform-methanol; 9:1, v/v), Rf 0.08.
Reaction SMILES: [CH3:1][CH:2]([CH2:8]C([O-])=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:12]Br>C(Cl)(Cl)(Cl)Cl.[Ag]>[Br:12][CH2:8][CH:2]([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: COC(=O)CC(C)CC(=O)[O-]
Agent: [Ag]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CC(C)CBr
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Methyl 3-methylglutarate(37 g; 231 mmol) was added to 1M NaOH (231 mL; 231 mmol) causing the solution to warm slightly. This solution was added to a solution of silver nitrate (39.2 g; 231 mmol) in water (184 mL) at 60° C. A fine white precipitate formed immediately. The mixture was cooled and stirred in an ice bath for 1 h before being filtered, washed with water, acetone and ether and partially dried on the filter. The solid was then dried over night at 80° C. in a vacuum oven to give the silver salt of the methyl 3-methylglutarate(49 g, 79%) as a pale brown solid. The silver salt of the methyl 3-methylglutarate (49 g; 184 mmol) was suspended in carbon tetrachloride (245 mL) and bromine (9.5 mL) slowly added. The reaction mixture warmed to ≈30° C. during this process and effervescence was seen. The reaction mixture was maintained at this temperature by the rate of addition of bromine. After the final addition of bromine the viscous mixture was stirred for 0.5 h before being heated at reflux for 1 h. After cooling, the pale yellow precipitate was removed by filtration and the filtrate washed with 1M aqueous sodium thiosulphate, brine, dried (phase separation paper) and concentrated under reduced pressure. This gave a pale yellow oil which contained 15% of methyl 3-methylglutarate as an impurity by 1H NMR. This was removed by taking the oil up in dichloromethane (DCM) and washing with 1M NaOH. Drying and concentration as above gave (±) methyl 4-bromo-3-methylbutyrate (25 g, 70%) as a pale yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH:38]=[N:37][N:36]=[N:35]3)[CH2:24][CH:23]2[OH:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH:38]=[N:37][N:36]=[N:35]3)[CH2:24][C:23]2=[O:39])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccccc3-n3cnnn3)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-n3cnnn3)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(tetrazol-1-yl)phenyl]piperidin-3-ol (0.6 g) obtained in Step 1 in 10 ml of dimethylsulfoxide, was added 0.48 ml of triethylamine (3.4 mmol). The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.54 g, 3.4 mmol) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 0.4 g of the titled compound.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([NH:24][C@@H:25]([CH3:30])[C:26]([O:28]C)=[O:27])[CH:5]=1)(=[O:3])[NH2:2].O[Li].O>C1COCC1.O>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([NH:24][C@@H:25]([CH3:30])[C:26]([OH:28])=[O:27])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)[C@H](C)Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(=O)O
Reaction time: 72 h
Yield: 40 %

Procedure:
To a solution of the (S)-methyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)propanoate (0.123 g, 0.300 mmol) in 5:1 THF/water (5 mL) was added LiOH.H2O (0.025 g, 0.60 mmol). After stirring 3 days, the reaction was quenched with 1N aqueous HCl (0.60 mL). The mixture was evaporated in vacuo then chromatographed using reverse-phase HPLC with a 40-100% acetonitrile in water (+0.1% TFA) gradient. The product fractions were pooled and concentrated to give a solid suspension. After cooling, the solid precipitate was filtered, rinsed with water and dried under vacuum at 50° C. to give (S)-2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)propanoic acid as a white powder (0.049 g, 0.12 mmol, 41% yield). 1H NMR (400 MHz, DMSO-d6): 12.57 (1H, s), 8.50 (2H, d, J=8.8 Hz), 8.29 (1H, s), 8.12 (1H, d, J=6.1 Hz), 7.76 (1H, s), 7.31-7.24 (2H, m), 7.18-7.12 (2H, m), 7.07 (1H, s), 7.03 (2H, d, J=8.8 Hz), 4.56 (1H, m), 1.44 (3H, d, J=7.5 Hz). LC/MS: m/z=397.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C@@H:16]([CH3:26])[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>[Pt].C(#N)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C@@H:16]([CH3:26])[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC#N
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
A 2-L, stainless-steel, Parr vessel was charged with platinum on carbon (5%, 4.0 g) and 10 mL of acetonitrile. A solution of 7-bromo-N-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-3-nitroquinolin-4-amine (40.5 g, 92.0 mmol) dissolved in 1 L of acetonitrile was then added. The reaction mixture was placed on Parr apparatus and shaken under H2 at 45 PSI (3.1×105 Pa) for 6 hours at ambient temperature. The reaction mixture was then filtered through a pad of CELITE filter agent. The pad rinsed with an additional 200 mL of acetonitrile and the combined filtrates were concentrated under reduced pressure to give 33.4 g 7-bromo-N4-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)quinoline-3,4-diamine as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8].[CH:13]1([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.N=C=N>>[CH:22]1([N:21]=[C:20]([NH:19][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:7][CH3:8])[O:9][CH3:10])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CNCCC[Si](OC)(OC)OC
Agent: N=C=N
Product: CO[Si](CCCN(C)C(=NC1CCCCC1)NC1CCCCC1)(OC)OC
Reaction time: 2 h

Procedure:
A mixture of 23.23 g of N-methyl-(3-(trimethoxysilyl)propyl)amine (0.12 mol, 20% excess) and of 20.65 g of dicyclohexylcarbodiimide (0.1 mol) was heated for 6 h at 100° C. (carbodiimide conversion of 94%). The final colorless mixture was devolatilized at 100° C. under 2 mbar for 2 h to give 41.3 g of a colorless, moderately viscous liquid corresponding to the expected guanidine, containing 6% of the initial amine.
Reaction SMILES: C([CH:3]([OH:22])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])=[CH:10][CH:9]=1)C>[O-2].[O-2].[Mn+4]>[F:20][C:16]([F:21])([CH:17]([F:18])[F:19])[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8](/[CH:7]=[CH:6]/[CH:5]=[CH:4]/[CH:3]=[O:22])=[CH:13][CH:12]=1
Reactant: CCC(O)/C=C/C=C/c1ccc(OCC(F)(F)C(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C/C=C/C=C/c1ccc(OCC(F)(F)C(F)F)cc1
Yield: 96 %

Procedure:
Ethyl (2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadien-1-ol was treated with active manganese dioxide in the same manner as in Reference example 22 to obtain the title compound having a melting point of 53 to 55° C. in a yield of 96%.
Reaction SMILES: [NH2:1][C:2]([N:9]([CH2:11][CH2:12][CH2:13][CH3:14])[CH3:10])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO>C(O)C>[NH2:5][C:4]1[S:6][N:1]=[C:2]([N:9]([CH2:11][CH2:12][CH2:13][CH3:14])[CH3:10])[C:3]=1[C:7]#[N:8]
Reactant: CCCCN(C)C(N)=C(C#N)C(N)=S
Agent: OO
Solvent: CCO
Product: CCCCN(C)c1nsc(N)c1C#N
Yield: 74.5 %

Procedure:
In the manner of Example XI, part C, 61 g of 3-amino-3-(butylmethylamino)-2-cyanopropenethioamide in 200 ml of ethanol were treated with 33 ml of 30% hydrogen peroxide (9.8 g of active H2O2) to yield 45 g of 5-amino-3-(butylmethylamino)-4-cyanoisothiazole, mp 87°-89°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[CH:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH:10]([O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:20]=[C:14]1[NH:15][C:16](=[O:19])[CH:17]=[CH:18][N:13]1[CH:11]1[CH:10]([O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9][CH:8]([CH2:7][OH:6])[O:12]1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1CC(OC(=O)c2ccccc2)C(n2ccc(=O)[nH]c2=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OC1CC(CO)OC1n1ccc(=O)[nH]c1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Compound 50.2 (0.713 g, 1.06 mmol) was dissolved in 10 ml anhydrous THF was cooled to 0° C. Tetrabutyl ammonium fluoride (1.11 ml, 1N in THF, 1.11 mmol) was added dropwise and the reaction mixture was allowed to rise to room temperature. The reaction was stirred for 4 hr at room temperature while monitoring by TLC. When the reaction was complete by TLC the, solvent was removed under vacuum. The residue was re-dissolved in ethyl acetate (4 ml) and purified by column chromatography. Yield 0.300 g, 65.0%. Anal. 1H-NMR (CD3CN): δ 2.2 m 1H; 2.45 m 1H; 3.37 t 1H; 3.7 dd 1H; 3.97 dd 1H; 4.53 m 1H; 5.62 m 1H; 5.87 d 1H; 6.06 s 1H; 7.49-7.70 m 5H; 7.79 t 1H; 8.05 t 4H; 8.19 d 1H.
Reaction SMILES: C(OC([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:9][NH:8][CH:7]=1)=O)C.[OH-].[Na+].[Na+].[Cl-]>C(O)CO>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[CH:6]=[CH:7][NH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(C)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: Cc1ccc(-c2cc[nH]c2)cc1
Temperature: 160 °C
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
Following a standard procedure (Balasubramanian, T. et al., J. Org. Chem. 2000, 65, 7919-7929), a mixture of 6 (6.81 g, 29.7 mmol) and ethylene glycol (76.0 mL) in a 250-mL Claisen flask was flushed with argon for 10 min, and then powdered NaOH (3.05 g, 76.2 mmol) was added. The flask was placed in an oil bath at 120° C. and the oil bath temperature was raised to 160° C. After 2.5 h, the flask was cooled to room temperature and 10% aqueous NaCl (150 mL) was added. The aqueous layer was extracted with CH2Cl2. The organic layers were collected, washed with 10% aqueous NaCl, dried (Na2SO4), concentrated, and chromatographed (silica, CH2Cl2) to give a light brown solid (3.33 g, 71%): mp 92-93° C.; 1H NMR δ 2.34 (s, 3H), 6.51-6.54 (m, 1H), 6.82-6.84 (m, 1H), 7.05-7.08 (m, 1H), 7.15 (d, J=7.8 Hz, 2H), 7.43 (d, J=7.8 Hz, 2H), 8.15-8.32 (br, 1H); 13C NMR δ 21.3, 106.7, 114.4, 119.0, 125.1, 125.4, 129.5, 133.1, 135.2; FAB-MS obsd 157.0885, calcd 157.0891 (C11H11N).