Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([OH:28])=[CH:25]2)=[CH:20][CH:19]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:24]1[CH:23]=[CH:22][C:21]2[C:26](=[CH:27][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:25]=1
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1ccc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2c1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (89 mg) and commercially available 7-methoxy-2-naphthol (209 mg) were mixed and stirred at 180° C. for 30 minutes, and the reaction mixture was then purified in the same manner as described in Example 2 to obtain 59 mg of the title compound (yield: 41%).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[SnH:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17].C(=O)=O.C([Cu])#N.[CH3:32][O:33][C:34](=[O:52])[C:35]#[C:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][O:47]1>C1COCC1.CO.CC(C)=O>[O:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH:46]1[O:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]/[C:36](/[Sn:13]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:35]\[C:34]([O:33][CH3:32])=[O:52]
Reactant: COC(=O)C#CCCCCCCCCOC1CCCCO1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: N#C[Cu]
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CO
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/C(=O)OC)CCCCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a flame-dried round-bottomed flask equipped with two dropping funnels was added iPr2NH (2.5 equiv, 71.4 mmol, 7.22 g, 10.0 mL) and THF (225 mL) and the solution was cooled to 0° C. nBuLi (2.5 equiv, 71.4 mmol, 44.6 mL of a nominally 1.6 M solution in hexanes) was added dropwise and the reaction was stirred for 30 min at 0° C. nBu3SnH (2.3 equiv, 65.6 mmol, 19.1 g, 17.7 mL) was added dropwise and the reaction was stirred for 30 min at 0° C. The reaction was cooled to −50° C. by the controlled addition of dry ice to acetone and CuCN (2.3 equiv, 65.6 mmol, 5.88 g) was added in one portion. The reaction was stirred for 45 min at −50° C. then cooled to −78° C. MeOH (1.70 mL) was added followed by the addition of methyl-11-[(tetrahydro-2H-pyran-2-yl)oxy]-undecynoate (1 equiv, 28.5 mmol, 8.46 g) in THF (85 mL) in one portion. The reaction was stirred at −78° C. for 10 min, then quenched with 170 mL of aq. NH4Cl/NH4OH (pH ˜8) and diluted with 150 mL Et2O. The reaction was warmed to rt (orange color is discharged and solution turns colorless), the layers were separated, and the aqueous layer extracted with Et2O (3×120 mL). The combined organic layers were washed with aq. NH4Cl/NH4OH (pH ˜8) (100 mL), and brine (120 mL), dried with Na2SO4, concentrated in vacuo, and purified by flash column chromatography (step gradient, Hex to 5% EtOAc/Hex) to afford (E)-methyl 11-((tetrahydro-2H-pyran-2-yl)oxy)-3-(tributylstannyl)undec-2-enoate (15.1 g, 25.5 mmol, 90%). TLC Rf=0.30 (5% EtOAc/Hex); 1HNMR (500 MHz): δ 5.86-6.03 (m, 1H), 4.56-4.62 (m, 1H), 3.85-3.92 (m, 1H), 3.74 (dt, 1H, J1=9.6 Hz, J2=6.9 Hz), 3.70 (s, 3H), 3.47-3.54 (m, 1H), 3.39 (dt, 1H, J1=9.6 Hz, J2=6.7 Hz), 2.78-2.97 (m, 2H). 1.79-1.90 (1H), 1.69-1.77 (1H), 1.27-1.65 (29H), 0.93-0.99 (5H), 0.91 (t, 9H, J=7.3 Hz); 13CNMR (125 MHz): δ 174.9, 164.6, 127.0, 98.8, 67.7, 62.3, 50.8, 35.3, 30.8, 29.8, 29.77, 29.68, 29.5, 29.0, 27.4, 26.3, 25.5, 19.7, 13.7, 10.0; FTIR: 2918, 2852, 1717, 1591, 1456, 1431, 1351, 1189, 1162, 1136, 1121, 1077, 1022, 867 cm−1; HRMS-ESI: calc. for C29H56NaO4Sn (M+Na)+: 611.3104. found: 611.3111.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].CC(O[CH2:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21])=O.B(O)(O)O>C(N(CC)CC)C.O>[NH2:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH2:9][S:3][C:1]([CH3:2])=[O:4])[CH2:19][S:18][C@H:13]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(O)=S
Agent: OB(O)O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
56.8 ml (0.8 mole) of thioacetic acid and 140 ml (1.0 mole) of triethylamine were added successively to three liters of water under stirring. The homogenous mixture was heated to 75° C. and there were added in one shot 100.0 g (0.368 mole) of 7-aminocephalosporanic acid (90%), causing a pH variation from 9.05 to 5.03. Thereafter there were added, first, 20 to 21 ml of triethylamine until a solution was formed and then 61.0 g of boric acid. Stirring was continued at 70° C. for 60 minutes and the reaction isoelectric pH was checked, regulating the variation from 5.80 to 5.60 by gradual addition of 10.9 ml of thioacetic acid over a period of about 30 minutes. During the last 15 minutes, the pH varied to a virtually constant value of 5.70. The precipitation increased during the reaction and was completed at 60° C. and the pH was adjusted to 4.80 (25° C.) by the addition of about 300 ml of 1N hydrochloric acid. The solid was filtered, washed successively with water and acetone to give 73.5 g of the compound of the title, with a 77% yield. It turned brown at about 215° C. and decomposed at 228° C. (polarised light). The excess thioacetic acid was recovered from the mother liquors at pH 1.0 by extraction with an organic solvent.
Reaction SMILES: [CH:1]1[C:6]2[S:7][C:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([O-:19])=[O:18])=[CH:16][C:11]=4[S:10][C:9]=3[C:5]=2[CH:4]=[CH:3][C:2]=1[C:20]([O-:22])=[O:21]>C1COCC1>[OH:22][CH:20]([OH:21])[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[S:10][C:11]4[CH:16]=[C:15]([CH:17]([OH:18])[OH:19])[CH:14]=[CH:13][C:12]=4[C:8]=3[S:7][C:6]=2[CH:1]=1
Reactant: O=C([O-])c1ccc2c(c1)sc1c3ccc(C(=O)[O-])cc3sc21
Solvent: C1CCOC1
Product: OC(O)c1ccc2c(c1)sc1c3ccc(C(O)O)cc3sc21
Reaction time: 8 h
Yield: 143.5 %

Procedure:
LiAIH4(0.74 g, 19.5 mmol) was added to [1]benzothieno[3,2-b]benzothiophene 2,7-dicarboxylate (1.50 g 3.9 mmol) in THF (40 mL). The mixture was stirred overnight. Insoluble materials were removed by filtration and washed with hot DMSO. The solution was precipitated in 50 mL of 1 normal (“N”) HCl. The product was collected by filtration to obtain 1.86 g (75%) of pure 2,7-bis(dihydroxymethyl)[1]benzothieno[3,2-b]benzothiophene.
Reaction SMILES: [CH:1]1(P)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[P:8]([Cl:13])(Cl)(Cl)(Cl)[Cl:9]>C1(C)C=CC=CC=1>[CH:1]1([P:8]([Cl:13])[Cl:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: PC1CCCCC1
Solvent: Cc1ccccc1
Product: ClP(Cl)C1CCCCC1

Procedure:
319 g (1.05 mol) of a 38 wgt % monocyclohexylphosphine solution in toluene was added dropwise at 25° C. to a suspension of 436 g PCl5 (2.1 mol) in 1 liter toluene. After the strongly exothermal reaction was complete, the reaction mixture was filtered using a reverse frit. 5 g orange colored solid matter remained behind. The clear solution (31P-NMR; δ P: 195 ppm, C6H11PCl2, 95 mol %) was distilled under vacuum.
Reaction SMILES: [CH3:1][N:2]([CH3:40])[C:3]1[C:8]([CH2:9][C:10]([O:12]C)=[O:11])=[C:7]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:6]=[C:5]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:29])=[CH:23][CH:22]=2)[N:4]=1.[OH-].[Na+]>CO>[CH3:40][N:2]([CH3:1])[C:3]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[C:7]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:6]=[C:5]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:29])=[CH:25][CH:26]=2)[N:4]=1
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(N2CCOCC2)c1CC(=O)O
Temperature: 60 °C
Yield: 62.4 %

Procedure:
A solution of methyl {4-(dimethylamino)-6-morpholin-4-yl-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.096 g, 0.18 mmol) in MeOH (2 mL) at room temperature was treated with 1N NaOH (1 mL) and the resulting mixture was heated at 60° C. for 5 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the remaining aqueous layer was washed with Et2O and acidified with 1N HCl. The separated solids were collected by suction, rinsed with water, and dried under vacuum to give {4-(dimethylamino)-6-morpholin-4-yl-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetic acid (0.059 g, 64% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.O=[C:25]([CH2:29][CH2:30][CH3:31])[CH2:26][C:27]#[N:28].CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:25]([CH2:29][CH2:30][CH3:31])[C:26]([C:27]#[N:28])=[C:16]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: CCCC(=O)CC#N
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1nc2ccc(O)cc2c(-c2ccccc2)c1C#N
Yield: 55.7 %

Procedure:
A solution of (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-phenyl)(phenyl)methanone (2.0 g, 6.1 mmol), 3-oxohexanenitrile (0.81 g, 7.3 mmol) and methanesulfonic acid (0.59 g, 6.1 mmol) in toluene (50 ml) was stirred at 110° C. for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from disopropyl ether to give 6-hydroxy-4-phenyl-2-propylquinoline-3-carbonitrile (0.98 g, yield 56%) as pale-yellow crystals.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17](F)=[CH:16][N:15]=[C:14]([NH:19][C:20]4C=CC=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[Br:27]C1C(NC2C=CC=C(O)C=2)=NC(Cl)=NC=1.C(N)C=C>>[CH2:20]([NH:19][C:14]1[N:13]=[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)[C:17]([Br:27])=[CH:16][N:15]=1)[CH:21]=[CH2:22]
Reactant: Oc1cccc(Nc2nc(Cl)ncc2Br)c1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Solvent: C=CCN
Product: C=CCNc1ncc(Br)c(Nc2cccc(O)c2)n1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 5-bromo-2-chloro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and allylamine were reacted to yield N2-allyl-5-bromo-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.08 (s, 1H), 7.21 (t, 1H, J=8.1 Hz), 7.02–6.97 (m, 2H), 6.71 (dd, 1H, J=2.4 and 8.7 Hz), 5.91–5.77 (m, 1H), 5.19–5.09 (m, 2H), 3.94–3.89 (m, 2H); LCMS: ret. time: 18.33 min.; purity: 99%; MS (m/e): 322 (MH+).
Reaction SMILES: Cl[C:2]1[N:31]=[CH:30][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH:25]1([N:22]2[CH2:21][CH2:20][CH:19]([O:18][C:15]3[CH:14]=[CH:13][C:12]([C:7]4[N:8]([CH3:11])[C:9](=[O:10])[C:4]5[CH:3]=[CH:2][N:31]=[CH:30][C:5]=5[N:6]=4)=[CH:17][CH:16]=3)[CH2:24][CH2:23]2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: [H][H]
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)nc2cnc(Cl)cc2c1=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)nc2cnccc2c1=O
Yield: 72.2 %

Procedure:
6-Chloro-2-{4-[(1-cyclopentylpiperidin-4-yl)oxy]phenyl}-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (11 mg, 0.025 mmol) produced in Example 30 and triethylamine (17 μL, 0.15 mmol) were dissolved in ethyl acetate (0.5 mL), and 10% palladium-carbon (3 mg) was added thereto and stirred in a hydrogen atmosphere at room temperature for 15 hours. The reaction solution was filtered through Celite, then the Celite was washed with ethyl acetate, and the mother liquid was concentrated. The residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the entitled compound (7.3 mg, 71%) as a pale brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:19][NH2:20]>CN(C=O)C>[CH3:19][N:20]1[CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][C:9](=[O:18])[CH2:10][CH:11]1[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: O=C(/C=C/c1ccncc1)/C=C/c1ccncc1
Reactant: CN
Solvent: CN(C)C=O
Product: CN1C(c2ccncc2)CC(=O)CC1c1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
A suspension of (1E,4E)-1,5-di(pyridin-4-yl)penta-1,4-dien-3-one (1 g, 3.2 mmol) in DMF (10 mL) was treated with N-methylamine (40% in H2O, 2.8 mL, 32 mmol) at 0° C. The solution was warmed up to ambient temperature and stirred for 6 h at RT. The reaction mixture was poured into ice-water and the resulting precipitate was filtered. The aqueous solution was extracted with DCM and the combined organic layers were dried with MgSO4, filtered and evaporated in vacuo. The crude product was purified by flash-chromatography (CH2Cl2/MeOH 9:1) to obtain NW-B591 as a bright yellow solid (417 mg, 48%) (note: mixture of cis/trans isomers in a ratio of 4:1). mp: 103-106° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.65 (dd, 4J=4.5 Hz, 3J=1.5 Hz, 4 H, HAr), 7.42 (dd, 3J=4.5 Hz, 4J=1.6 Hz, 4 H, HAr), 3.51 (dd, 3J=12.0 Hz, J=3.2 Hz, 2 H, CH2), 2.82-2.68 (m, 2 H, CH), 2.57-2.46 (m, 2 H, CH2), 1.89 (s, 3 H, CH3). Signals of the minor isomer: 8.65-8.60 (m, 4 H, HAr), 7.25 (dd, 3J=4.7 Hz, 4J=1.5 Hz, 4 H, HAr), 4.13 (t, 3J=6.0 Hz, 2 H, CH), 2.96-2.86 (m, 2 H, CH2), 2.86 (ddd, J=7.9, J=6.0 Hz, J=1.2 Hz, 2 H, CH2), 2.19 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 204.3 (C), 151.6 (C), 150.4 (CH), 122.2 (CH), 68.9 (CH), 49.6 (CH2), 41.1 (CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH:9]([CH2:10]I)[CH2:8][C:7]1=[O:12].[CH:19]([NH2:21])=O.[C-]#N.[Na+]>>[C:19]([CH2:10][CH:9]1[N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7](=[O:12])[CH2:8]1)#[N:21]
Reactant: NC=O
Reactant: COc1ccc(CN2C(=O)CC2CI)c(OC)c1
Agent: [C-]#N
Agent: [Na+]
Product: COc1ccc(CN2C(=O)CC2CC#N)c(OC)c1
Yield: 70 %

Procedure:
A solution of 1.2 g. (3.3 mmoles) of 1-(2,4-dimethoxybenzyl)-4-(iodomethyl)-2-azetidinone prepared according to Example 13 in 5 ml. ofddimethyl formamide is stirred with 0.35 g. (7 mmoles) of sodium cyanide for 48 hours, at room temperature. The solution is then poured onto 30 ml. of water and extracted with five 20-ml. portions of ether. The ethereal solution is dried with magnesium sulfate, decolored with activated carbon, filtered and the filtrate is evaporated in vacuo. 0.6 g. (70%) of the named compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:16][N:17]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1.CCN(CC)CC.[Cl:43][C:44]1[C:45]([OH:55])=[C:46]([S:51](Cl)(=[O:53])=[O:52])[CH:47]=[C:48]([Cl:50])[CH:49]=1>C(Cl)Cl>[Cl:43][C:44]1[C:45]([OH:55])=[C:46]([S:51]([NH:1][CH2:2][C:3]2[CH:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)[CH:6]=[C:5]([CH2:16][N:17]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:4]=2)(=[O:53])=[O:52])[CH:47]=[C:48]([Cl:50])[CH:49]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(CN)cc(-c3ccc(F)cc3)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(CNS(=O)(=O)c3cc(Cl)cc(Cl)c3O)cc(-c3ccc(F)cc3)c2)cc1
Yield: 51.6 %

Procedure:
To a solution of N-((5-(aminomethyl)-4′-fluorobiphenyl-3-yl)methyl)-N-(4-fluorobenzyl)-4-methylbenzenesulfonamide (40 mg, 0.081 mmol) and Et3N (40 mg, 0.395 mmol) in CH2Cl2 (4 mL) at rt was added solid 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (21.24 mg, 0.081 mmol) with stirring. The reaction was complete within an hour. The mixture was concentrated and the residue was purified by prep HPLC to provide the desired product as a white solid (30 mg). 1H NMR (CDCl3): δ 7.72 (d, J=8.2 Hz, 2H), 7.51 (d, J=2.2 Hz, 1H), 7.34-6.83 (m, 14H), 5.32 (t, J=6.0 Hz, 1H), 4.25 (s, 2H), 4.245 (s, 2H), 4.12 (d, J=6.0 Hz, 2H), 2.43 (s, 3H); MS (ESI): (M+H)+=717.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[C:18]4[CH:39]=[CH:38][C:37]([CH2:40][NH2:41])=[CH:36][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].CC[O:50]CC>C(OCC)(=O)C>[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[C:18]4[CH:39]=[CH:38][C:37]([C:40](=[O:50])[NH2:41])=[CH:36][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCC
Reactant: NCc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 99 %

Procedure:
3-[[4-[2-(1-Piperidinyl)ethoxy]phenyl]methyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene-6-methanamine (Part C) was dissolved in 50 mL of ethyl acetate and added to a solution of 100 mg of oxalic acid in 30 mL of ethyl acetate. After adding 10 mL of ether to the solution, the precipitate was filtered to give 1.05 g (99%) of a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Yield: 33.9 %

Procedure:
A procedure similar to that described in Preparation 66 was repeated, except that 15 g of 2-chloro-3-nitropyridine, 13.22 g of aniline and 25.07 g of sodium carbonate were reacted in 180 ml of toluene. After working up the product as described in Preparation 66, the resulting crude product was purified by column chromatography through silica gel, using a 1:5 by volume mixture of ethyl acetate and hexane, to give 6.9 g of the title compound, melting at 66-68° C.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17](F)[C:16]=1[CH3:25]>C1COCC1.O>[F:14][C:15]1[C:16]([CH3:25])=[C:17]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: Nc1ccccn1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
Potassium tert-butoxide (2.59 g, 23.1 mmol) was added to a solution of 2-aminopyridine (1.14 g, 12.1 mmol) in THF (30 mL) at 0° C. and the reaction mixture stirred at 0° C. for 20 min. 1,3-Difluoro-2-methyl-4-nitrobenzene (2 g, 11.6 mmol) was added as a solution in THF (10 mL) and the reaction mixture stirred at 0° C. for 30 min. The reaction mixture was diluted with water and the product extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a yellow solid (2 g, 70%). 1H NMR 400 MHz δ (CDCl3): 8.53 (1H, br s), 8.19 (1H, ddd, J=5.1, 1.9, 0.8 Hz), 8.02 (1H, dd, J=9.2, 5.7 Hz), 7.57 (1H, ddd, J=8.2, 7.3, 1.9 Hz), 6.94 (1H, dd, J=9.1, 8.2 Hz), 6.86 (1H, ddd, J=7.3, 5.1, 1.0 Hz), 6.69 (1H, dt, J=8.3, 0.9 Hz), 2.06 (3H, d, J=2.8 Hz).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.[C:38]1(=O)[CH2:41][CH2:40][CH2:39]1>ClC(Cl)C>[CH:38]1([N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:24][CH:23]=3)[CH2:19][CH2:20]2)[CH2:41][CH2:40][CH2:39]1
Reactant: O=C(C=Cc1ccc(OC2CCNCC2)cc1)N1CCOCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(C=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.3 %

Procedure:
Sodium triacetoxyborohydride (38.6 grams, 0.18 moles) was added in a single lot to a well stirred solution of 3-[4-(Piperidin-4-yloxy)phenyl]-1-(morpholin-4-yl)prop-2-ene-1-one (19.1 grams, 0.060 moles, obtained in preparation 1) and cyclobutanone (6.8 mL, 0.09 moles) in dichloroethane (500 mL). The mixture was further stirred at room temperature for 6 hours. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the mass was quenched on to water (1000 mL) and basified with 40% lye solution (pH˜9). The layers were separated and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic layer was washed with brine solution (250 mL), dried over sodium sulfate, concentrated under vacuum and the residual mass was further purified by flash chromatography using methanol:triethylamine:chloroform in the ratio of 1.5:0.25:98.25 to obtain the title compound (17.4 grams).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C:7]2=[O:8])[O:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.C(Cl)Cl.[Cl-].[Na+].O.CCOCC>[CH3:1][C:2]1([CH3:11])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][CH:7]2[OH:8])[O:3]1
Reactant: CC1(C)O[C@@H]2COC(=O)[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CC1(C)O[C@@H]2COC(O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
The reduction of 2,3-O-isopropylidene-D-erythronolactone (2) was performed using a modified version of Cohen's procedure (see: Cohen, N.; et al J. Am. Chem. Soc. 1983, 105, 3661-3672). Diisobutylaluminum hydride (101 mL of a 1.5 M soln. in toluene, 152 mmol) was added in a dropwise fashion via an addition funnel to a cold (-78° C.) solution of 2,3-O-isopropylidene-D-erythronolactone (2) (see: Cohen, N.; et al in Organic Synthesis, Collective Vol, IV; J. P. Freeman, Ed.; Wiley, N.Y., 1990; pp 297-301) (20.0 g, 126 mmol) in CH2Cl2 (360 mL). After 2 h, methanol (20 mL) was added, followed by brine (10 mL). After warming to room temperature, the mixture was diluted with ether (500 mL) and MgSO4 (150 g) was added. After stirring vigorously for 4 h, the mixture was filtered with suction through a sintered glass funnel, and the filter cake was washed with ether (100 mL). The filtrate was concentrated to give 17.0 g (84%) of crude 2,3 -O-isopropylidene-D-erythrose as a pale yellow oil that was used without further purification.