Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][CH:35]([F:46])[O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41].Cl.CN(C)CCCN=C=NCC>CC#N>[F:34][CH:35]([F:46])[O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:41]
Reactant: O=C(O)c1cccc(OC(F)F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(OC(F)F)c4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-difluoromethoxy benzoic acid (0.45 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was then washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford 3-difluoromethoxy-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a white solid (0.64 g, 65%): mp, 164-166° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.6 min (99%); 1H NMR (DMSO-d6): δ 2.04-2.09 (m, 1H), 2.53-2.64 (m, 2H), 2.85-2.93 (m, 1H), 4.92 (d, J=6.0 Hz, 2H), 5.14-5.20 (dd, J=5, 12 Hz, 1H), 6.97-7.86 (m, 8H), 8.97 (t, J=6.0 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.91, 38.29, 48.86, 113.18, 116.60, 119.08, 120.02, 121.91, 125.34, 127.12, 128.74, 129.58, 131.48, 131.54, 113.18, 116.60, 119.08, 120.02, 121.91, 125.34, 127.12, 127.74, 128.58, 131.48, 131.54, 132.96, 134.64, 138.89, 147.66, 165.60, 166.94, 167.51, 169.81, 172.73. Anal Calcd for C22H17F2N3O6: C, 57.77; H, 3.75; N, 9.19; F, 8.31. Found: C, 57.62; H, 3.60; N, 8.99; F, 8.32.
Reaction SMILES: [H-].[K+].[C:3]1([CH:13]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][N:17]3[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[S:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C1COCC1>[CH3:28][N:29]([CH3:33])[C:30]([O:20][C:19]1[C:18]2=[CH:21][CH:22]=[CH:23][N:17]2[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14][C:13]=1[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)=[O:31]
Reactant: O=C1c2cccn2-c2ccccc2SC1c1cccc2ccccc12
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C(=O)OC1=C(c2cccc3ccccc23)Sc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a suspension of potassium hydride (0.167 g, 1.46 mmol, 35% in oil) in anhydrous THF (4.0 mL) was added the the (±)-6-(1-naphthyl)pyrrolo[2,1-d][1,5]benzothiazepin-7(6H)-one (500 mg, 1.46 mmol) dissolved in anhydrous THF (5 mL). The reaction mixture was stirred at rt for 2 h, and then dimethylcarbamoyl chloride (0.181 g, 1.68 mmol) was slowly added. After stirring for 8 h at 30° C., the solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed (dichloromethane) to give the PBOX-8 in 82% yield. IR (neat) 1725 cm−1; 1HNMR (CDCl3) δ 2.43 (s, 3 H), 2.58 (s, 3 H), 6.45 (m, 1 H), 6.64 (m, 1 H), 7.18-7.57 (m, 10 H), 7.77-7.86 (m, 2 H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH2:36])=[N+:2]=[N-:3].[Cl:37][C:38]1[CH:39]=[C:40]2[C:45](=[C:46]([Cl:48])[CH:47]=1)[CH2:44][N:43]([CH3:49])[CH2:42][CH:41]2[C:50]1[CH:51]=[C:52]([S:56](Cl)(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH:36][S:56]([C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([CH:41]2[C:40]3[C:45](=[C:46]([Cl:48])[CH:47]=[C:38]([Cl:37])[CH:39]=3)[CH2:44][N:43]([CH3:49])[CH2:42]2)[CH:51]=1)(=[O:58])=[O:57])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN=[N+]=[N-])c2)C1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of 32-azido-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontan-1-amine (436.9 mg, 0.777 mmol) in dry DMF (3.5 mL) under N2 was cooled to 0° C. A solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (300 mg, 0.706 mmol) and DIEA (273.2 mg, 2.118 mmol) in DMF (3 mL) was added dropwise. After 60 minutes LCMS indicated complete conversion and the solvent was removed to give N-(32-azido-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (620 mg) as a yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:5]=34)[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: CC1COc2c(N3C[C@H](C)[C@H](NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A mixture of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (0.5 g), anhydrous dimethyl sulfoxide (10 ml) and cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.54 g) was stirred for 2 hours at 90°-100° C. and then concentrated. To the residue was added methanol and the resulting precipitate was collected by filtration and then washed with cold methanol to give the title compound (0.58 g) as yellowish powder, mp 219°-220° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[C:11]1([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([OH:26])[CH2:21]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:26][CH:20]1[CH2:19][C:18]2[C:22](=[CH:23][CH:24]=[CH:25][C:17]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:21]1)=[O:8]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)C(C(=O)OC2Cc3cccc(-c4ccccc4)c3C2)C1(C)C
Yield: 63.2 %

Procedure:
In a manner similar to Example 12A, the reaction of 1.09 g (0.007 mole) of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride and 1.5 g (0.007 mole) of (+)-4-phenyl-2-indanol (EE≥95%) in the presence of 0.7 g (0.009 mole) of pyridine and 20 ml of toluene gave 1.48 g of (+)-4-phenyl-2-indanyl 2,2,3,3-tetramethylcyclopropanecarboxylate, EE≥95%. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(C1C=C(/C=C\C2C=CC=CC=2)C=CC=1)(=[O:28])CCCCC>>[C:16]1([CH2:15][CH2:14][CH:10]([CH2:11][CH2:12][CH3:13])[CH2:9][C:8]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:28])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCCC(=O)c1cccc(/C=C\c2ccccc2)c1
Reactant: CCCCCC(=O)c1cccc(/C=C/c2ccccc2)c1
Product: CCCC(CCc1ccccc1)CC(=O)c1ccccc1

Procedure:
This compound was prepared by the catalytic reduction (H2, 10% Pd-C, ethanol) of either trans-3-hexanoyl stilbene, cis-3-hexanoyl stilbene or, 3-hexanoyl diphenyl acetylene in nearly quantitative yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:49]([O:48][C:47]([NH:46][C@H:41]1[CH2:42][C@@H:43]([CH3:45])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1)=[O:53])([CH3:50])([CH3:51])[CH3:52]
Reactant: O=C(Nc1cc2ccc(N3CCCCC3=O)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCCCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(2-oxopiperidin-1-yl)quinoline-2-carboxylic acid (0.015 g, 0.036 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.013 g, 0.043 mmol) and HATU (0.034 g, 0.089 mmol) in DMF (0.3 mL), DIPEA (0.019 mL, 0.11 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, then purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound (0.005 g, 20%). LCMS calc. for C39H46N7O6 [M+H]: m/z=708.3. found: 708.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:28]3[C@H:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
N,N'-Carbonyldiimidazole (1 g) is added to a solution of 2-methoxyphenylacetic acid (1 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 40 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2 g) and triethylamine (1.7 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.8 cm, height 13 cm), eluting with ethyl acetate and collecting 25 cc fractions. Fractions 3 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (5 cc) and isopropyl ether (10 cc). The crystals are drained, washed with isopropyl ether (25 cc) and dried. (3aR,7aR)-(-)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone (1.7 g) is obtained in the form of white crystals melting at 200° C.; [α]20D =-274° (c=0.49, acetic acid).
Reaction SMILES: [CH2:1]([CH:8]([C:14](=O)[CH3:15])[C:9](OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:21][C:22]([NH2:24])=[NH:23]>C(O)C>[NH2:24][C:22]1[N:23]=[C:9]([OH:10])[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([CH3:15])[N:21]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: Cc1nc(N)nc(O)c1Cc1ccccc1

Procedure:
A mixture of ethyl 2-benzyl-3-oxobutanoate (6 g, 27.2 mmol), guanidine carbonate (2.94 g, 16.3 mmol) and ethanol (20 ml) was refluxed for 10 hours. After cooling, the precipitate was filtered and washed with water, ethanol and ether in order, to the object compound (3.62 g, 61.7%).
Reaction SMILES: O1CCOCC1.CO.C([NH:11][CH:12]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>>[NH2:11][CH:12]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(CCC(NC=O)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(CCC(N)c2cccnc2)cc1
Temperature: 60 °C
Yield: 87.4 %

Procedure:
To 10 ml of the solution of 0.62 g of methyl 4-[3-formamido-3-(3-pyridyl)propyl]benzoate methanol-1,4 dioxane (1:1) was added 5 ml of 4% sulfuric acid, and stirred under heating at 60° C. overnight, which was then poured into saturated aqueous sodium hydrogencarbonate solution to be extracted with ethyl acetate. The obtained ethyl acetate phase was washed in saturated aqueous sodium chloride and dried over magnesium sulfate, to distill off the solvent, so that 0.35 g of methyl 4-[3-amino-3-(3-pyridyl)propyl]benzoate was yielded.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[CH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])[CH:5]=[CH:6][C:7]=1[O:8][CH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]([CH3:31])[CH3:32])=[O:29])=[CH:26][CH:25]=1
Reactant: CN(C)C(=O)c1ccc(CCl)cc1
Reactant: O=C(c1ccc(O)c(F)c1)N1CCC[C@H]1CN1CCCC1
Product: CN(C)C(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2F)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C from (3-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)methanone and 4-chloromethyl-N,N-dimethyl-benzamide [CAS 121083-51-0]. MS (ES+) 454.2
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[CH2:30]([CH2:32][NH2:33])[OH:31].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:33][CH2:32][CH2:30][OH:31]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCO
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H](NCCO)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 91.7 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and ethanolamine (2.7 ml, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[2-hydroxyethylamino]-cholestan-3β-ol as a white solid (9.4 g, 98%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 17% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([F:17])[C:7]=1[N:8]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]1.[Cl:25][C:26]1[C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C>ClCCl>[Cl:25][C:26]1[C:31]([C:32]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:4]2[CH:5]=[C:6]([F:17])[C:7]([N:8]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]3)=[C:2]([F:1])[CH:3]=2)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1)c1cccnc1Cl

Procedure:
A mixture of 3′,5′-difluoro-4′-[3-(trifluoromethyl)-1H-pyrazol-1-yl][1,1′-biphenyl]-2-amine (i.e. the product of Step D; 0.17 g, 0.52 mmol), 2-chloro-3-pyridinecarbonyl chloride (0.092 g, 0.52 mmol) and triethylamine (0.050 g, 0.52 mmol) in dichloromethane (5 mL) was stirred for 16 h at room temperature. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes. The resulting solid was triturated with 1-chlorobutane and hexanes to yield the title compound (0.090 g), a compound of the present invention.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH:32]([CH3:35])[CH2:33]Cl)[CH2:27][CH2:26]1>>[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH:32]([CH3:35])[CH2:33][O:1][C:2]2[C:11]3[C:6](=[C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:18])[C:3]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:27][CH2:26]1
Reactant: O=c1oc2c(-c3ccccc3)cccc2c(O)c1-c1ccccc1
Reactant: CC(CCl)CN1CCOCC1
Product: CC(COc1c(-c2ccccc2)c(=O)oc2c(-c3ccccc3)cccc12)CN1CCOCC1
Yield: 69.1 %

Procedure:
Prepared according to the method of Example 8, by alkylation of 4-hydroxy-3,8-diphenyl-coumarin with 3-morpholino-2-methyl-1-chloropropane. After recrystallisation from ethanol, a solid melting at 120°-121° C. is obtained. Yield 69.1%.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3]([NH2:6])=[N:4][CH3:5].[CH:8]1([N:14]=[C:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[CH:8]1([NH:14][C:15]([N:6]=[C:3]([NH:4][CH3:5])[N:2]([CH3:7])[CH3:1])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C=NC1CCCCC1
Reactant: CN=C(N)N(C)C
Solvent: Cc1ccccc1
Product: CNC(=NC(=O)NC1CCCCC1)N(C)C

Procedure:
To 60.6 parts by weight of 1,1,2-trimethylguanidine in 600 parts by volume of toluene are added dropwise with cooling 75 parts by weight of cyclohexyl isocyanate. After evaporation of the solvent in vacuo, the product is recrystallized from acetonitrile to yield 2-cyclohexylcarbamoyl-1,1,3-trimethylguanidine, m.p. 121°-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:22])[N:7]2[CH3:21].Br[C:24]1[CH:25]=[C:26]([CH2:30][OH:31])[CH:27]=[N:28][CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:31][CH2:30][C:26]1[CH:25]=[C:24]([C:11]2[C:3]([O:2][CH3:1])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:21])[C:6](=[O:22])[CH2:5]3)[CH:29]=[N:28][CH:27]=1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
Reactant: OCc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1c(-c2cncc(CO)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 37a (80 mg, 0.264 mmol) was added (5-bromo-pyridin-3-yl)-methanol (CAS#37669-64-0, 55 mg, 0.29 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.330 mL, 066 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (120 mg, 0.013 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was partially purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 10%). Further purification was accomplished via reverse phase HPLC (7 to 40% acetonitrile/water w/0.1% NH4OH) to furnish 5-(5-hydroxymethyl-pyridin-3-yl)-4-methoxy-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 285.1240 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 3.24 (s, 3H), 3.75 (s, 3H), 3.78 (s, 2H), 4.71 (s, 2H), 6.84 (d, J=81 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H)