Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.[CH3:11][O:12][C:13]1C=C2C(=C[CH:22]=1)C(=O)CCC2>>[CH3:11][O:12][C:13]1[CH:22]=[C:5]2[C:4](=[CH:3][CH:2]=1)[CH:9]([NH2:10])[CH2:8][CH2:7][CH2:6]2
Reactant: NC1CCCc2occc21
Reactant: COc1ccc2c(c1)CCCC2=O
Product: COc1ccc2c(c1)CCCC2N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 6-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.34, 6.78, 6.63, 3.97, 3.79, 2.74, 1.77, 1.89; 13C NMR (100 MHz, CDCl3) δ 158.47, 138.45, 133.91, 129.64, 113.71, 112.67, 55.61, 49.23, 34.25, 30.31, 24.6, 23.23, 19.87.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].[C:6]([O-:9])(=[O:8])[CH3:7].[Na+].C(O)(=O)C>C(#N)C.[Ru](Cl)(Cl)Cl>[C:6]([O:9][CH:4]1[NH:1][C:2](=[O:5])[CH2:3]1)(=[O:8])[CH3:7]
Reactant: O=C1CCN1
Reactant: CC(=O)[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)OC1CC(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
0.71 g of azetidine-2-one and 0.82 g of anhydrous sodium acetate were suspended in 20 ml of acetonitrile and cooled to -5°, to which 10 ml of acetonitrile containing 0.26 g of ruthenium trichloride.3H2O was added. 3.8 ml of acetic acid containing 40% peracetic acid was carefully dropped thereto so as to maintain the temperature not higher than 0° C., then continuously stirred at 0° C. for 30 minutes. The solvent was distilled off under reduced pressure at a temperature not higher than 40° C., and subjected to silica gel chromatography (eluent: n-hexane: ethyl acetate=1:1) for purification to obtain 0.92 g of the title compound (yield 71%).
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13].[CH3:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:34])[CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:20][C:18]=2[N:19]=1.CCN(CC)CC>CCO>[OH:34][C@@H:26]([CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:17]2[S:16][C:15]([CH3:14])=[N:19][C:18]=2[CH:20]=1)[CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]2=[O:13])[CH2:32][CH2:33]1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Reactant: O=C1C(Cl)CCN1c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(C4CCN(c5ccccc5)C4=O)CC3)ccc2s1
Temperature: 85 °C
Reaction time: 60 h

Procedure:
To a solution of 3-chloro-1-phenylpyrrolidin-2-one (100 mg, 0.51 mmol) in EtOH (10 mL) was added 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as prepared in Example 3A (190 mg, 0.62 mmol) and Et3N (0.2 mL, 1.43 mmol). The solution was stirred at 85° C. for 60 hours. Upon cooling, the solution was concentrated to an oil and purified via flash column chromatography to afford 3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-phenylpyrrolidin-2-one.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:23]([C:45]4[CH:57]=[CH:56][C:55]5[C:54]6[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=6)[C:48]([CH2:62][CH2:63][CH2:64][CH3:65])([CH2:58][CH2:59][CH2:60][CH3:61])[C:47]=5[CH:46]=4)[C:24]4[CH:36]=[CH:35][C:34]5[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[C:27]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:37][CH2:38][CH2:39][CH3:40])[C:26]=5[CH:25]=4)=[CH:10][C:11]=3[C:12]2([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[CH:66]([C:68]1[S:72][C:71](B(O)O)=[CH:70][CH:69]=1)=[O:67]>>[CH2:37]([C:27]1([CH2:41][CH2:42][CH2:43][CH3:44])[C:26]2[CH:25]=[C:24]([N:23]([C:9]3[CH:8]=[CH:7][C:6]4[C:5]5[C:13](=[CH:14][CH:2]=[CH:3][CH:4]=5)[C:12]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=4[CH:10]=3)[C:45]3[CH:46]=[C:47]4[C:55]([C:54]5[CH:53]=[CH:52][C:51]([C:71]6[S:72][C:68]([CH:66]=[O:67])=[CH:69][CH:70]=6)=[CH:50][C:49]=5[C:48]4([CH2:58][CH2:59][CH2:60][CH3:61])[CH2:62][CH2:63][CH2:64][CH3:65])=[CH:56][CH:57]=3)[CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:38][CH2:39][CH3:40]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(Br)ccc3-4)cc21
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(N(c3ccc4c(c3)C(CCCC)(CCCC)c3ccccc3-4)c3ccc4c(c3)C(CCCC)(CCCC)c3cc(-c5ccc(C=O)s5)ccc3-4)cc21

Procedure:
As shown in Scheme 3, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31); and 2-Iodo-9H-fluorene is reacted with 1-iodobutane to form 9,9-dibutyl-2-iodo-9H-fluorene (32). Then, 7-bromo-9,9-dibutyl-9H-fluoren-2-ylamine (31) is reacted with 9,9-dibutyl-2-iodo-9H-fluorene (32) by Ullman coupling reaction to obtain (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33). Next, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-bis-(9,9-dibutyl-9H-fluoren-2-yl)amine (33) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a). Finally, in acetonitrile, 5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophene-2-carbaldehyde (34a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 3-(5-{7-[bis-(9,9-dibutyl-9H-fluoren-2-yl)amino]-9,9-dibutyl-9H-fluoren-2-yl}-thiophen-2-yl)-2-cyano-acrylic acid (35a).
Reaction SMILES: [CH3:1][C:2]1([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[C@H:20]1([NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[NH2:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]1[NH:27][CH:16]1[CH2:17][CH2:18][N:13]([C:2]2([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:14][CH2:15]1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: CCOC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3N)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
To a solution ethyl 4-methyl-4-(4-oxo-1-piperidyl)piperidine-1-carboxylate (336 mg, 1.25 mmol) and (1S,2S)-cyclohexane-1,2-diamine (286 mg, 0.5 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (398 mg, 1.88 mmol) and stirred at room temperature for 12 h. Saturated NaHCO3 (5 mL) was added, the phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by passing through a short silica gel pad (5-10% MeOH in dichloromethane) to afford the title compound (87 mg, 19%). MS (M+1): 367.31.
Reaction SMILES: [C:1]([C:3]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:3]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2cc(CN3CCC(C#N)(c4ccccn4)CC3)c3ccccn3c2=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccccn2)CCN(Cc2cc(C(=O)NC3CCCNC3)c(=O)n3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-[({1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-4H-quinolizin-3-yl}carbonyl)amino]piperidine-1-carboxylate (0.335 g, 0.587 mmol) in 12 mL of dichloromethane at 0° C. was added trifluoroacetic acid (1.17 mL, 15.2 mmol). The mixture was warmed to rt, and after 2 h, treated with saturated aqueous sodium bicarbonate and extracted 3× with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory and a high resolution mass spectrum (ES+) m/z of 471.2504 calculated for M+H+ [C27H31N6O2: 471.2503]: 1H NMR (400 MHz, CDCl3) δ 9.93 (d, J=7.5 Hz, 1H), 9.38 (d, J=7.3 Hz, 1H), 8.60 (s, 1H), 8.55 (d, J=4.0 Hz, 1H), 8.14 (d, J=9.0 Hz, 1H), 7.71-7.61 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.27-7.19 (m, 2H), 4.21-4.18 (m, 1H), 3.78 (s, 2H), 3.30-3.27 (m, 1H), 3.00-2.76 (m, 4H), 2.63-2.53 (m, 3H), 2.29-2.21 (m, 2H), 2.05-1.86 (m, 3H), 1.85 (br s, 1H), 1.70-1.53 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].Cl.[CH2:40]([N:47]([CH2:50][CH2:51]Cl)[CH2:48][CH3:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:51][CH2:50][N:47]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:48][CH3:49])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Reactant: CCN(CCCl)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCN(CC)Cc3ccccc3)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
To a solution of N-[1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (200 mg, 0.39 mmol) in DMSO (8 ml) were added 2-(N-benzyl-N-ethylamino)ethyl chloride hydrochloride (182 mg, 0.78 mmol) and potassium t-butoxide (132 mg, 1.17 mmol), and the mixture was stirred at room temperature for five hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (218 mg, 0.32 mmol).
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])[CH3:8])C(C)C.[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11]1.C1(N)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:7]1([NH:3][C:15]([C:12]2[CH:13]=[CH:14][NH:10][CH:11]=2)=[O:17])[CH2:9][CH2:8]1
Reactant: O=C(O)c1cc[nH]c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cc[nH]c1

Procedure:
Following the same procedure in Example 31, step B, using DIPEA (0.87 mL, 0.65 g, 5.0 mmol), 1H-pyrrole-3-carboxylic acid (0.25 g, 2.3 mmol), cyclopropylamine (0.14 g, 2.5 mmol) and HATU (1.0 g, 2.7 mmol) in DMF (10 mL). The crude product was purified by MPLC using EtOAc on silica gel to 52 mg (15%) of the title product. 1H NMR (400 MHz, METHANOL-D4) δ 0.42-0.63 (m, 2 H), 0.66-0.83 (m, 2 H), 2.60-2.80 (m, 1 H), 6.49 (dd, J=2.93, 1.56 Hz, 1 H), 6.69 (dd, J=2.73, 1.95 Hz, 1 H), 7.30 (t, J=1.76 Hz, 1 H).
Reaction SMILES: [Na].CC1C(C[S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=O)=NC=CC=1OCC1(C)OCC2(OCCO2)CO1.CC1(C)OCC(COC2C(C)=CN=[C:45]([CH2:50][OH:51])C=2C)CO1.O.CC1(C)OCC(COC2C(C)=CN=C(CO)C=2C)C[O:57]1>C1(C)C=CC=CC=1>[NH:29]1[C:28]2[CH:30]=[C:31]3[O:51][CH2:50][CH2:45][O:57][C:32]3=[CH:33][C:27]=2[N:26]=[C:25]1[SH:23]
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: Sc1nc2cc3c(cc2[nH]1)OCCO3

Procedure:
The same procedure as in the steps (5f) to (5h) was repeated using the (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol, which was obtained by subjecting (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol monohydrate obtained in the same manner as in Example 96(5) to azeotropic distillation with toluene, and 6,7-dihydro-1H-[1,4]dioxino[2′,3′:4,5]benzo[d]imidazole-2-thiol, to obtain the title compound (395 mg, total 61.7% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].[CH2:8]([SH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[Na+].[Na+].II>C(OCC)C.O>[CH2:8]([S:15][S:7][C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCS
Reactant: Cc1occc1S
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCSSc1ccoc1C
Reaction time: 0.33 h

Procedure:
0.57 Grams (0.0050 moles) of 2-methyl-3-furanthiol and 1.32 grams (0.01 moles) of n-heptylmercaptan are dissolved in 12 ml of diethyl ether. 0.8 Grams (0.0075 moles) of sodium carbonate dissolved in 8 ml water is added to the reaction mass. Over a period of 20 minutes, a solution of 1.9 grams (0.0075 moles) of iodine dissolved in 6 ml diethyl ether is added to the reaction mass with stirring until the iodine color remains. The reaction mass is then stirred over a period of 35 minutes.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19])=[O:4].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]2[N:9]3[CH:20]=[N:21][CH:22]=[C:8]3[CH:7]=[N:6][C:5]=2[C:3]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:4])=[C:13]([F:19])[CH:14]=1
Reactant: C=COCCON
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a stirred solution of 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (150 mg, 0.41 mmol) and O-(2-vinyloxy-ethyl)hydroxylamine (127 mg, 1.23 mmol, 3.0 eq) in anhydrous THF (7.5 mL) at 0° C. was added lithium hexamethyldisilazide (1M in THF, 1.2 mL, 1.23 mmol, 3.0 eq.), and the reaction, mixture was stirred at room temperature. After 1 h the reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate and diluted with ethyl acetate. The organic layer was isolated and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 5% methanol in dichoromethane) to give an oil. Crystallization from DCM—ether—hexane afforded the desired product as a pale orange solid (160.2 mg, 89.4%). LCMS (method C): RT=2.53 min, [M+H]+=437/439.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.O>CN(C=O)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:8][CH2:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: OCCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCCOCCc1ccco1
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
2-Furanethanol (2 g) in DMF (5 ml) was added dropwise to a suspension of sodium hydride (0.43 g) in DMF (20 ml). The mixture was stirred for 30 min and added dropwise to 1,6-dibromohexane (21.8 g). The resulting suspension was heated at 60°-70° for 18 h, poured into water (200 ml) and extracted with diethyl ether (3×100 ml). The dried extract was evaporated and the residue was purified on a column of silica eluted with cyclohexane. The resulting oil was fractionally distilled (Kugelrohr) to give the title compound as a colourless oil (1.7 g) b.p. 75°-80°/0.3 Torr.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][N:28]=[C:3]([CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:4]=3)[S:10][C:11]=2[C:17]([CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(CN4CCOCC4)c3)nc12
Temperature: 25 °C
Yield: 60 %

Procedure:
2-Chloromethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide (300 mg, 0.72 mmol) and morpholine (2.1 ml, 25 mmol) are heated to 30° C. for 30 min. The mixture is then cooled to room temperature, treated with dichloromethane (15 ml) and saturated aqueous sodium carbonate (15 ml), the phases are separated and the aqueous layer extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (silica, eluent chloroform/ethyl acetate, then chloroform/methanol) afforded the title compound as white solid (60% yield). MS: m/e=469(M+H+), mp 199-201° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al].Cl[CH:21](Cl)[CH2:22][Si:23]([Cl:26])([Cl:25])[Cl:24]>C(=S)=S.CCCCCC>[Cl:24][Si:23]([CH2:22][CH:21]1[C:12]2[CH:11]=[CH:10][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][C:7]=2[C:1]2[C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2)([Cl:26])[Cl:25]
Reactant: c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Reactant: ClC(Cl)C[Si](Cl)(Cl)Cl
Agent: [Al]
Solvent: S=C=S
Solvent: CCCCCC
Product: Cl[Si](Cl)(Cl)CC1c2ccccc2-c2cc(-c3ccccc3)ccc21
Yield: 15 %

Procedure:
In the same apparatus and procedures as Example 1 above, 5.0 g (21.7 mmol) of meta-terphenyl and 0.47 g (17.4 mmol) of aluminum foil were alkylated in CS2 (50 ml) solution with (2,2-dichloroethyl)-trichlorosilane 6.68 g (21.7 mmol) under dry nitrogen atmospheric pressure for 24 hr at reflux temperature. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and CS2 were distilled, recrystallization from ether yielded 1.27 g of 9-(trichlorosilyl)methyl-3-phenylfluorene (yield; 15%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][O-:14].[Na+]>CO.CCCCCC>[Cl:12][C:4]1[N:3]=[C:2]([O:14][CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (20.0 g, 96.1 mmol) in MeOH (100 mL) was added 0.5 M NaOMe in MeOH (423 mL, 211 mmol) dropwise. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was then concentrated to ca. ⅓ of the volume and slowly poured into saturated NH4CI solution (200 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined EtOAc extracts were dried (Na2SO4), and concentrated in vacuo to yield a tan solid which was suspended in hexane (500 mL) and sonicated for 10 min. The resulting solid was collected by suction filtration and dried under suction to yield 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine as a powder. 1H-NMR (400 MHz, CDCl3) δ: 6.39 (s, 1H), 6.28 (br s, 2H), 4.05 (s, 3H).
Reaction SMILES: B1([C@H]2[C@H](C)[C@@H]3C(C)(C)[C@H](C3)C2)C2CCCC1CCC2.[Cl:20][CH2:21][C:22]([C:24]1[CH:25]=[N:26][C:27]([N:30]2[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]2[CH3:36])=[CH:28][CH:29]=1)=[O:23]>>[Cl:20][CH2:21][C@@H:22]([C:24]1[CH:25]=[N:26][C:27]([N:30]2[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]2[CH3:36])=[CH:28][CH:29]=1)[OH:23]
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)CCl)cn1
Agent: C[C@@H]1[C@H]2C[C@H](C[C@H]1B1C3CCCC1CCC3)C2(C)C
Product: Cc1ccc(C)n1-c1ccc([C@@H](O)CCl)cn1
Temperature: 0 °C
Reaction time: 96 h
Yield: 37.3 %

Procedure:
(R)-Alpine borane (1.5 L, 0.5 M in tetrahydrofuran) was added slowly to a cooled (0° C.), neat, 2-chloro-1-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-3-yl]-ethanone (Example 140; 93 g). The mixture was warmed to room temperature and reduced to one third its original volume by distilling tetrahydrofuran. After four days, the mixture was cooled to 0° C. and 3 M aqueous solution of K2CO3 (600 mL) was added. Then the reaction mixture was oxidized by drop wise addition of 30% H2O2 (250 mL). After stirring at room temperature for 3 h, the reaction mixture was diluted ethyl acetate, organic layer was separated. Aqueous portion was extracted (ethyl acetate), combined organic extracts were washed with water and dried. After concentration in vacuo, the resulting oil was purified by chromatography on silica gel (hexanes/ethyl acetate as eluent) to afford a yellow solid (35 g). 1H NMR (CDCl3, 300 MHz) δ 8.59 (m, 1H), 7.88 (dd, 8.1 Hz, 2.2 Hz, 1H), 7.26 (m, 1H), 5.91 (m, 2H), 4.96 (m, 1H), 3.78 (m, 2H), 3.35 (br s, 1H), 2.11 (2, 6H); MS (FAB) m/z 251 (MH+); Anal. calcd for C13H15N2OCl: C, 62.28; H, 6.03; N, 11.17. Found: C, 61.95; H, 6.03; N, 10.92; Rf=0.4 (60:40 hexanes/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: Clc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
4'-Chlorobiphenyl-4-carboxylic acid chloride (Musante and Parrini, Gazz, Chim. ital., 1949, 49, 453) was reacted with chlorobenzene by the method of Example 7, to give 4-chlorophenyl 4'-chloro-4-biphenylyl ketone identical with that described in Example 8.
Reaction SMILES: C([NH:11][S:12]([N:15]1[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]2[CH2:26][CH:16]1[CH2:17][CH2:18]2)(=[O:14])=[O:13])(OCC1C=CC=CC=1)=O>CO.[Pd]>[NH2:11][S:12]([N:15]1[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]2[CH2:26][CH:16]1[CH2:17][CH2:18]2)(=[O:14])=[O:13]
Reactant: CCOC(=O)C1C2CCC(C2)N1S(=O)(=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1C2CCC(C2)N1S(N)(=O)=O
Reaction time: 3 h
Yield: 87 %

Procedure:
A solution of ethyl N-(carbobenzyloxyaminosulfonyl)-2-azabicyclo[2,2,1]heptan-3-carboxylate (40.35 g; 105.51 mmol) in methanol (300 ml) under nitrogen was cooled to 0° C. and 2.5 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated for 3 hours at 50 psi. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo and purified by flash silica gel chromatography (35-40% ethyl acetate/hexane) to afford 22.79 g (87%) of ethyl N-(aminosulfonyl)-2-azabicyclo[2,2,1]heptan-3-carboxylate (Formula VII: R=Ethyl; R1 =H; R2 and R3 together = ##STR19## as a solid.