Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2[nH]c(C3CCNCC3)nc2-c2ccncc2)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Fc1ccc(-c2[nH]c(C3CCN(Cc4ccccc4)CC3)nc2-c2ccncc2)cc1
Yield: 35.2 %

Procedure:
To a stirring solution of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]piperidine (0.51 mmol, 0.20 g) in acetonitrile (4.0 mL) and methanol (2.0 mL) was added sodium bicarbonate (1.8 mmol, 0.15 g) and benzyl chloride (0.51 mmol, 64.0 mg). The reaction was heated to reflux overnight, cooled, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was chromatographed over silica, eluting with 2.5% to 10% MeOH:CH2Cl2. The product containing fractions were evaporated under reduce pressure and crystallized from diethyl ether to give 74 mg of the title compound as a white powder. mp=212°-215° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Agent: Cl
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CN1CCCCC1)CO2

Procedure:
Preparation according to Example 3 using [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 1 mmol), piperidine (1 ml) and ACN (3 ml). Yield: 0.3 g, 94%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 227° C. MS m/z (rel. intensity, 70 eV) 311 (M+, 1), 310 (M+, 1), 99 (7), 98 (bp), 79 (2), 55 (4). [α]=−65° (MeOH).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH:16]2[CH2:23][CH:22]3[CH:18]([CH2:19][N:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21]3)[NH:17]2)[CH:5]=1.[C:29](O)(=O)C.C=O.O.C([BH3-])#N.[Na+]>CO>[CH3:29][N:17]1[CH:16]([CH2:15][C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([N:4]4[CH:3]=[N:2][N:1]=[CH:5]4)[CH:7]=3)[NH:11][CH:10]=2)[CH2:23][CH:22]2[CH:18]1[CH2:19][N:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21]2
Reactant: CC(=O)O
Reactant: CCOC(=O)N1CC2CC(Cc3c[nH]c4ccc(-n5cnnc5)cc34)NC2C1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1CC2CC(Cc3c[nH]c4ccc(-n5cnnc5)cc34)N(C)C2C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86 %

Procedure:
To a stirred solution of (1RS,3RS,5RS)-3-[{5-(1,2,4-triazol-4-yl)-1H-indol-3-yl}methyl]-2,7-diazabicyclo[3.3.0]octane-7-carboxylic acid, ethyl ester (1.6514 g, 4.34 mmol) in methanol (70 mL) was added glacial acetic acid (0.99 mL, 17.3 mmol), 37% solution of formaldehyde in water (0.423 mL, 5.64 mmol) and sodium cyanoborohydride (0.3309 g, 5.27 mmol). The mixture was stirred at room temperature under argon for 3.5 h before quenching with saturated K2CO3 solution (200 mL) and extracting with EtOAc (3×50 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, CH2Cl2 --MeOH--NH3 (aq); 95:5:0.5 then 94:6:0.6) to give 1.4723 g (86.0%) of the title compound as a cream solid. δH (250 MHz, CDCl3) 1.23 (3H, t), 1.63 (1H, m), 1.84-1.96 (1H, m), 2.52 (3H, s), 2.59 (1H, m), 3.78 (1H, m), 4.10 (2H, q, J=7.0 Hz), 7.14-7.20 (2H, m), 7.50 (1H, d, J=12.6 Hz), 7.52 (1H, s), 8.48 (2H, s), 8.63 (1H, br s). m/e (ES+) 395 (M+H)+.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].ClCC[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:16]([CH2:17][CH2:18][C:35](=[O:36])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH2:26][CH2:27]1
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCC(=O)c2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 3-chloro-1-phenyl-propan-1-one and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:14]/[C:15]1[NH:16][CH:17]=[C:18]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[C:19]=1[CH3:20])/[C:5](=[O:13])[NH:6]2.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd]>[CH3:12][O:11][C:10]1[C:2]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:13])/[C:4]/2=[CH:14]\[C:15]1[NH:16][CH:17]=[C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:19]=1[CH3:20]
Reactant: COc1ccc2c(c1Br)/C(=C/c1[nH]cc(C(=O)N3CCOCC3)c1C)C(=O)N2
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2c(c1-c1ccccc1)/C(=C/c1[nH]cc(C(=O)N3CCOCC3)c1C)C(=O)N2
Temperature: 85 °C
Reaction time: 8 h
Yield: 9.5 %

Procedure:
To a mixture of 4-bromo-5-methoxy-3-[1-[3-methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one (223 mg, 0.5 mmol) and phenylboronic acid (73 mg, 0.6 mmol) in DME/water (5 mL) were added Palladium catalyst Pd(PPh3)2Cl2 (10.5 mg) and sodium carbonate (106 mg, 1 mmol). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 85° C. oil bath for overnight. TLC showed some de-bromination of the starting material. The degass procedure was repeated for three more times and the heating was continued for 3 more days. The mixture was cooled to room temperature, the unreacted starting material was filtered off and the mother liquor was concentrated. The residue was purified on a silica gel column to give 21 mg of 5-methoxy-3-[1-[3-methyl 4 (morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-4-phenyl-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl.[N:33]1([C:38](=N)[NH2:39])C=CC=N1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:38]([NH2:39])=[NH:33])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=N)N)CC4)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.193 g, 0.65 mmol) in dichloromethane (10 mL) and Hunig's Base (0.34 mL, 1.95 mmol) was added 1H-pyrazole-1-carboximidamide hydrochloride (0.100 g, 0.69 mmol). The reaction mixture was stirred at room temperature for 2 hours. A white precipitates was formed, which was filtered, washed with dichloromethane and hexane to give the desired product, 3-(4-methoxy-benzyl)-3,6,8,9-tetrahydro-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamidine as a white solid (0.088 g, 40%). M.p.=255-256° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.35 (s, 1H), 8.26 (s, 1H), 7.63 (s, 4H), 7.22-7.16 (m, 2H), 6.88-6.82 (m, 2H), 5.60 (s, 2H), 4.75 (s, 2H), 3.76 (t, J=6.4 Hz, 2H), 3.69 (s, 3H), 3.21 (t, J=6 Hz, 2H); LCMS [M+H]: 337.
Reaction SMILES: [ClH:1].C(C1C=CC(C2[O:14]C(C#N)=CC=2)=CC=1)#N.Cl.Cl.[NH:19]=[C:20](OC)[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([C:32](=[NH:35])OC)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C([O-])(=O)C.[NH4+:42].[NH4+:43].[OH-]>CO>[OH2:14].[ClH:1].[ClH:1].[C:20]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([C:32]([NH2:35])=[NH:43])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)(=[NH:42])[NH2:19]
Reactant: COC(=N)c1ccc(-c2ccc(C(=N)OC)o2)cc1
Reactant: N#Cc1ccc(-c2ccc(C#N)o2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: N=C(N)c1ccc(-c2ccc(C(=N)N)o2)cc1
Product: O
Reaction time: 3 h
Yield: 83 %

Procedure:
Dry HCl was passed into a solution of 5-(4-cyanophenyl)-2-furonitrile (10 g, 0.052 mole) in absolute methanol (100 ml) with stirring at 10°-15° for 3 hours until saturated. The product was collected by filtration; yield: 12 g (71%). A mixture of methyl 5-(4-[imino(methoxy)methyl]phenyl)-2-furimidate dihydrochloride (12 g, 0.036 mole), ammonium acetate (140 g) and absolute alcohol (550 ml) was refluxed for 6 hours and stored overnight at room temperature. The mixture was poured onto ice, adjusted to pH 8 with NH4OH and the solution concentrated to one half its volume. More H2O (800 ml) was added and the product was collected by filtration. After air drying, the product was dissolved in isopropanol, adjusted to pH 3 with ethanol-HCl and ether was added until cloudiness appeared. The solution was cooled and the solid was collected by filtration to yield 9 g (83%) of 5-( 4-amidinophenyl)-2-furamidine dihydrochloride monohydrate, m.p. > 300°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)Nc1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Yield: 76 %

Procedure:
A solution of 7-(3-aminophenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.32 g, 0.9 mmol) in acetic anhydride (3 ml) was stirred at ambient temperature for one hour. Saturated, aqueous sodium carbonate was added and the resultant mixture was extracted with ethyl acetate. This organic extract was washed with water and brine, successively, dried over magnesium sulphate, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (97:3, v/v) to afford the desired product (0.27 g, 76%) m/z, 396.1 (M+H)+.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[CH2:30][CH2:31][CH3:32]>C1COCC1>[CH2:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:35][CH:34]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1ccc(C=O)cc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1ccc(C=CCCCCC(=O)O)cc1
Yield: 51.3 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and p-butylbenzaldehyde (3.24 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (2.67 g, 51%) as a colorless oil (bp 154-157° C./0.05 torr) . IR: 3400-2500, 1720 cm-1, 1H-NMR:0.92 (t, 3 H), 1.50 (m, 8 H), 2.30 (m, 4 H), 2.58 (m, 2 H), 5.58+6.15 (m, 1 H), 6.38 (t, 1 H), 7.18 (m, 4 H), 10.30 (bs, 1 H). Anal. Calcd. for C17H24O2 : C, 78.42, H, 9.29%; Found: C, 78.38, H, 9.29%. Z:E=62:38.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:22][C:23]5[O:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=5)[C:14]4=[O:31])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1.Cl.[CH3:33][NH:34][CH3:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>CN(C)C=O>[CH3:33][N:34]([CH3:35])[C:28]([C:26]1[N:27]=[C:23]([CH2:22][N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]3([C:8]4[C:9](=[CH:10][C:5]5[O:4][N:3]=[C:2]([CH3:1])[C:6]=5[CH:7]=4)[O:11][CH2:12]3)[C:14]2=[O:31])[O:24][CH:25]=1)=[O:30]
Reactant: CNC
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2nc(C(=O)O)co2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2nc(C(=O)N(C)C)co2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
A mixture of 2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid (0.32 g, 0.76 mmol), dimethylamine hydrochloride (0.13 g, 1.52 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.21 g, 1.07 mmol), 4-methylmorpholine (0.23 mL, 2.07 mmol) and anhydrous N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo, and the residue recrystallized from diethyl ether to afford N,N-dimethyl-2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide (0.23 g, 68%) as a colorless solid: mp 87-89° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.48-7.5 (m, 1H), 7.31-7.25 (m, 1H), 7.14-7.11 (m, 1H), 7.05-6.95 (m, 3H), 5.28-5.06 (m, 3H), 4.87-4.84 (m, 1H), 3.32 (s, 3H), 3.06 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 175.8, 164.0, 161.7, 158.2, 157.1, 154.9, 143.7, 141.3, 137.2, 130.1, 129.5, 124.0, 123.9, 123.2, 118.0, 109.3, 108.6, 107.9, 81.3, 56.3, 38.4, 37.5, 36.2, 9.8; MS (ES+) m/z 444.8 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:21](=[O:22])[O:23][CH2:24][CH:25]3[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:31]4[C:26]3=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(=O)OCC3c4ccccc4-c4ccccc43)C2=O)cc1

Procedure:
The title compound 26e was prepared from compound 76 (101 mg, 0.25 mmol), Fmoc chloride (71 mg, 0.28 mmol) and DIPEA (131 μL, 0.75 mmol) in a manner similar to that described for 25a in 96.4% (124 mg) yield as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH:7]1[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:12]=1)=[O:5])[CH3:2].C=O.CO.[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([CH3:27])[CH:7]1[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[N:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNC1c1cc(C)nc(-n2ccnc2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C)C1c1cc(C)nc(-n2ccnc2)n1
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
2-(2-Imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-3-carboxylic acid ethyl ester (300 mg, 0.996 mmol), formaldehyde, 37 wt % in H2O (500 μL), methanol (8 mL) and acetic acid (550 μL) were all combined in a reaction vessel and stirred for 30 mins. Next, sodium triacetoxyborohydride (530 mg, 2.49 mmol) was added and the solution was allowed to stir at room temperature for an additional 30 mins. After this period of time, the reaction mixture was concentrated under vacuum, dissolved in ethyl acetate (75 mL) and poured into ice (25 mL). The pH was adjusted to pH=8 with 1M NaOH. The organic layer was partitioned from the aqueous layer, dried over Na2SO4 and concentrated down to afford the crude product. The product was purified by Flash Chromatography (0-10% methanol/DCM gradient) to afford 130 mg (42%) 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-methyl-pyrrolidine-3-carboxylic acid ethyl ester. [M+H]+ 316.56.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)=[O:6].CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-].O1CCNC1>O>[CH3:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]=[C:5]2[NH:4][CH2:3][CH2:2][O:6]2)=[CH:9][CH:10]=1
Reactant: CSc1ccc(NC(=O)NCCCl)cc1
Agent: C1COCN1
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Product: CSc1ccc(N=C2NCCO2)cc1
Temperature: 25 °C

Procedure:
A suspension of 15 g. (0.06 mole) of N-(2-chloroethyl)-N'-(4-methylthiophenyl)urea and 3 drops of Triton® X-100 surfactant, a polyoxyethylated derivative of alkylphenol, in 500 ml. of water is refluxed in 11/4 hours. The solution is cooled to room temperature and filtered. The filtrate is basified with ammonium hydroxide in order to precipitate the desired product. The product is filtered, washed with water, and air dried to yield 9 g. (70% of theory) of the desired oxazolidine, m.p. 124°-126° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH2:3]1.[CH3:15][I:16]>C1C=CC=CC=1>[I-:16].[CH3:14][C:2]1([CH3:1])[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][CH2:10][N+:11]([CH3:15])([CH3:12])[CH3:13])[CH2:3]1
Reactant: CI
Reactant: CC1CC(CCN(C)C)CC(C)(C)C1
Solvent: c1ccccc1
Product: CC1CC(CC[N+](C)(C)C)CC(C)(C)C1
Product: [I-]
Yield: 93.1 %

Procedure:
To a solution of [2-(3,3,5-trimethylcyclohexyl)ethyl]dimethylamine (1.0 g) in benzene (30 cc) was added methyliodide (2.0 g), and the mixture was allowed to stand over night. Precipitated crystals were gathered by filtration and recrystallized from a mixed solvent of benzene and ether to give colorless crystals (1.6 g) of [2-(3,3,5-trimethylcyclohexyl)ethyl]trimethylammonium iodide, m.p. 263°-265° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[CH2:5][OH:6].[OH:15][CH2:16][C:17]1[CH:18]=C(C)C=C[C:22]=1S([O-])(=O)=O.[CH3:28]N(C)C=O>>[F:3][C:4]([F:14])([C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])[CH2:5][O:6][CH2:22][C:17]1([CH3:18])[CH2:28][O:15][CH2:16]1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CO)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC1(COCC(F)(F)C(F)(F)C(F)(F)F)COC1
Reaction time: 0.75 h

Procedure:
A 50 weight percent dispersion of sodium hydride 6.1 grams (127 mmol) in mineral oil, was washed twice with hexanes and was suspended in 60 milliliters of dimethyl formamide. Then 24.0 grams (120 mmol) of 2,2,3,3,4,4,4-heptafluorobutan-1-ol was added and mixture was stirred for 45 minutes. A solution of 25.0 grams (97.5 mmol) of 3-hydroxymethyl-p-toluenesulfonate in 15 milliliters of dimethyl formamide was added and the mixture was heated at 75°-85° C. for 30 hours when 1HNMR analysis of an aliquot showed that the starting sulfonate had been consumed.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([NH:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1
Reactant: Nc1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A solution of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenylamine hydrochloride (76 mg, 0.209 mmol), triethylamine (29 uL, 0.209 mmol) and methanesulfonyl chloride (19.3 uL, 0.249 mmol) in dry pyridine (3 mL) was stirred at ice bath temperature for 1 hr and then at RT for 2 hrs. The reaction mixture was evaporated, re-evaporated from toluene, dissolved in EtOAc, washed with H2O, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography with a 0-25% gradient of ethyl acetate in hexanes and lyophilized to yield 48 mg of N-[3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenyl]-methanesulfonamide as a white amorphous powder. LC-MS (ES) calculated for C20H16F3NO3S, 407.41; found m/z 406 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[F:13][C:14]([F:29])([S:25](F)(=[O:27])=[O:26])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18].[OH-].[K+]>>[F:29][C:14]([F:13])([S:25]([O:4][CH2:3][C:2]([F:12])([F:1])[C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9])(=[O:27])=[O:26])[C:15]([F:23])([F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Product: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
2,2,3,3,4,4,4-heptafluorobutan-1-ol (200 g, 1.0 mol, obtained from 3M Company) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (300 g, 1.0 mol, obtained from 3M Company) were combined in a 1-liter, 3-necked round bottom flask. The flask was equipped with an overhead mechanical stirrer, cold water condenser, thermocouple and an addition funnel. Aqueous potassium hydroxide (45 percent by weight in water, 154 g, 1.05 mol) was added dropwise via the addition funnel at such a rate that the temperature did not exceed 35° C. Once the addition of the potassium hydroxide was complete, the mixture was stirred for 16 hours at room temperature. Precipitated salts were then filtered from the mixture and the lower liquid fluorochemical product phase was separated from the upper aqueous phase and washed once with water to give 350 g crude product. The product was distilled at atmospheric pressure and the distillation cut boiling from 140-150° C. used without further purification (96.3 percent purity by GC).