Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:19])C(=O)C1>OS(C(F)(F)F)(=O)=O>[Br:19][C:7]1[C:6]([O:10][CH3:11])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: COc1cccc(F)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)C(F)(F)F
Product: COc1c(Br)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Fluoro-6-methoxybenzonitrile (8.30 g, 54.9 mmol) was dissolved in Triflic acid (75 mL) at 0° C. then NBS (10.3 g, 57.7 mmol) was added. The reaction mixture was stirred at RT for 1 h. LC-MS showed no starting material peak. The reaction mixture was poured into ice and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by chromatography through a 330 g Redi-Sep column and eluted with 10% to 50% EtOAc/hexane solvent system to yield the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH2:21])[CH2:13]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:2]([CH3:22])([O:4][C:5]([N:7]1[CH2:8][CH2:9][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH:21][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:13]2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(NS(C)(=O)=O)c1ccccc12

Procedure:
A sample of 1'-(1,1-Dimethylethyloxycarbonyl)-3-amino-2,3-dihydrospiro(1H-indene-1,4'-piperidine), prepared by hydrogenation of 500 mg of oxime (1.58 mmole) as in Example 135 Step A, in 3.5 mL methylene chloride containing 475 mg of DMAP (2.46×1.58 mmole), and 550λ of triethylamine (2.51×1.58 mmole), was stirred under nitrogen in an ice bath while adding a solution of 270λ of methanesulfonyl chloride (2.2×1.58 mmole) in 3 mL methylene chloride dropwise over 2-3 minutes. The suspension was stored over night in the refrigerator. It was then washed twice with water, dried with magnesium sulfate and concentrated under reduced pressure to a gum. Preparative TLC on four 8"×8"×1,000 g GF silica gel plates using 1:2 ethyl acetate: hexane afforded the title compound, which crystallized on standing. Yield: 322 mg (54%)
Reaction SMILES: C[O:2][C:3](=[O:55])[C:4]([CH3:54])([CH3:53])[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:19][CH2:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])=[CH:14][CH:13]=2)[C@@H:9]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:32]=3[CH:42]=2)[CH2:8][N:7]1[S:43]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:45])=[O:44].[OH-].[Li+]>C1COCC1.CO>[CH3:24][O:23][CH2:22][C@H:21]([CH3:25])[CH2:20][O:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:10]2[C@@H:9]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]4[O:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:32]=4[CH:42]=3)[CH2:8][N:7]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:44])=[O:45])[C@H:6]([CH2:5][C:4]([CH3:54])([CH3:53])[C:3]([OH:55])=[O:2])[CH2:11]2)=[CH:13][CH:14]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)OC)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 1.0 mmol of 3-[(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid methyl ester in 10 ml of THF and 10 ml of MeOH are added 10 ml of a 3M lithium hydroxide solution. The reaction mixture is stirred for 4 h at 65° C. The organic solvents are evaporated under reduced pressure and the remaining solution is acidified with 3M aqueous HCl until pH 2. This mixture is extracted with 100 ml of EtOAc (3×). The combined organic layers are washed with brine and dried with Na2SO4. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a pale orange foam. Rf=0.28 (EtOAc/heptane/HCOOH 2:1:0.1); Rt=5.50 (gradient I).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:19]([NH:23][OH:24])([CH3:22])([CH3:21])[CH3:20]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[O-:24]
Reactant: CCCCCCCI
Reactant: N#Cc1ccc(O)cc1F
Reactant: CC(C)(C)NO
Product: CCCCCCCOc1ccc(C=[N+]([O-])C(C)(C)C)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 28 using 2-fluoro-4-hydroxybenzonitrile, 1-iodoheptane and N-tert-butylhydroxylamine. The title compound was isolated in 66.0% overall yield as a white solid, m.p. 38.8° C. (Rf=0.21 on a silica gel plate using hexanes/ethyl acetate, 4:1, v:v, as the eluant).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]>>[CH:11]([C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1)=[CH:12][CH2:13][CH2:14][CH3:15]
Reactant: C=CCCCBr
Reactant: C1=Cc2ccccc2C1
Product: CCCC=CC1=CCc2ccccc21

Procedure:
Metallocenes MET 1, MET 3, and MET 4 were produced using suitable procedures. MET 2 was synthesized by first reacting lithiated indene with 5-bromo-1-pentene. Pure 3-(1-pentenyl) indene was obtained via vacuum distillation as a pale yellow oil. One mole of 3-(1-pentenyl) indene was added to diethyl ether and cooled to −74° C., and one mole of n-butyllithium was added. The reaction mixture was stirred at 21° C. for 3 hr, then cooled again to −74° C., followed by the addition of a diethyl ether solution of dichloro(diisopropylamino) boron, and then stirred for 12 hr while warming to 21° C. The resulting yellow slurry was centrifuged, and the bright yellow solution was poured off and solvent removed under reduced pressure. Monochloro(diisopropylamino)-3-(1-pentenyl)indenylboron was obtained as a yellow oil. One mole of monochloro(diisopropylamino)-3-(1-pentenyl)indenylboron was added to tetrahydrofuran and cooled to 0° C., followed by the addition of one mole of sodium cyclopentadiaenide, producing a yellow slurry, which was stirred at 21° C. for 12 hr. The reaction solution was centrifuged and then decanted off. Concentration under reduced atmosphere yielded the ligand shown below as a yellow oil:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:31]([NH2:36])[CH2:32][CH2:33][CH2:34][CH3:35].C[CH2:38][OH:39]>>[CH2:31]([NH:36][C:38](=[O:39])[NH:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:5])[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCN
Reactant: CCO
Reactant: Nc1ccccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: CCCCCNC(=O)Nc1ccccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 29.9 %

Procedure:
{2-amino-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide and n-pentylamine}:yield 29.9%; mp 178°-180° C. (EtOH); 1NMR (DMSO-d6)ppm: 0.86 (3H, t), 1.24-1.83 (13H, m), 2.79 (2H, d), 2.96 (2H, dd), 3.15 (2H, t, ), 4.26 (1H, s), 6.91 (1H, t), 7.13-7.41 (12H, m), 7.57 (1H, d), 8.22 (1H, d), 8.58 (1H, t), 9.93 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([OH:27])=O)[CH:21]=2)[CH:15]=1)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:65][O:66][C:67](=[O:79])[C@H:68]([CH2:70][CH2:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[NH2:69].Cl>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([NH:69][CH:68]([CH2:70][CH2:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C:67]([O:66][CH3:65])=[O:79])=[O:27])[CH:21]=2)[CH:15]=1)=[O:8]
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (Example 32)(140 mg, 0.35 mmol) in 10 ml of anhydrous DMF were added HATU (160 mg, 0.42 mmol) and N,N-diisopropylethylamine (135 mg, 1.05 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of L-Glutamic acid 5-tert-butyl 1-methyl ester hydrochloride (135 mg, 0.53 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. 2M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 5-tert-butyl 1-methyl 2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)pentanedioate as white solid. Yield: 170 mg, 81%.
Reaction SMILES: [Br:1][CH2:2]C.[C:4]([O:7][C@H:8]1[C@@H:13]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][C@H:11]2[C@H:20]3[C@H:30]([CH2:31][CH2:32][C@:9]12[CH3:10])[C@:28]1([CH3:29])[C@H:23]([CH2:24][CH2:25][C@@H:26]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:27]1)[CH2:22][CH2:21]3)(=[O:6])[CH3:5]>ClCCl.C(OCC)C>[Br-:1].[C:4]([O:7][C@H:8]1[C@@H:13]([N+:14]2([CH3:2])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:12][C@H:11]2[C@H:20]3[C@H:30]([CH2:31][CH2:32][C@:9]12[CH3:10])[C@:28]1([CH3:29])[C@H:23]([CH2:24][CH2:25][C@@H:26]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:27]1)[CH2:22][CH2:21]3)(=[O:6])[CH3:5]
Reactant: CCBr
Reactant: CC(=O)O[C@H]1[C@@H](N2CCCCC2)C[C@H]2[C@@H]3CC[C@H]4CC[C@@H](N5CCCCC5)C[C@]4(C)[C@H]3CC[C@@]21C
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)O[C@H]1[C@@H]([N+]2(C)CCCCC2)C[C@H]2[C@@H]3CC[C@H]4CC[C@@H](N5CCCCC5)C[C@]4(C)[C@H]3CC[C@@]21C
Product: [Br-]
Reaction time: 7.5 h
Yield: 25.1 %

Procedure:
Bromoethane (1.5 g) was added to a solution of 2β,16β-di-(1-piperidinyl)-5α-androstan-17β-ol acetate (1.0 g) in a mixture of dry dichloromethane (10 ml) and dry diethyl ether (10 ml). The solution was sealed in a pressure bottle and set aside at room temperature for 7.5 h. The solvent was then removed under reduced pressure, without heating, to afford a white solid, which was dissolved in the minimum of dry dichloromethane (8.0 ml) and dry diethyl ether (30 ml) was added to precipitate the crude product (0.3 g). The material from the mother liquor was retreated with bromomethane (1.05 g) in dry dichloromethane (7.0 ml) and dry diethyl ether (7.0 ml), as above, to yield a further quantity (0.3 g) of crude product. The procedure was repeated once again to obtain a final amount (0.25 g) of crude product. The three crops were combined and crystallised from dichloromethaneacetone to afford 1-[17β-acetyloxy-2β-(1-piperidinyl)-5α-androstan-16β-yl]-1-methyl-piperidinium bromide (0.30 g), m.p. 213°-219° C.; [α]D -19.5° (c 0.36 in CHCl3).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)[CH:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1(=[O:36])[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>CN(C1C=CN=CC=1)C.ClCCCl>[C:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][CH:16]([O:19][C:26](=[O:36])[C:27]4[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:29]([OH:31])=[O:30])[CH2:17][CH2:18]3)[CH:10]=[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)OC1CCN(c2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1

Procedure:
The title compound was prepared by reacting 1-(2,6-diphenyl-pyrimidin-4-yl)-piperidin-4-ol (0.25 g, 0.75 mmol) with pthalic anhydride (0.335 g, 2.0 mmol) in presence of DMAP (0.13 g, 10 mmol) in solvent DCE (10 mL) at refluxing temperature for 2 hours, followed by column purification.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:13][OH:14])[C:5]2=[N:4][CH:3]=1.CS[C:17]1[N:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[CH:20]=[CH:19][N:18]=1.[CH3:36][NH2:37]>>[CH3:36][NH:37][C:17]1[N:22]=[C:21]([C:2]2[N:6]3[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][CH2:13][OH:14])[C:5]3=[N:4][CH:3]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CN
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: OCCNc1nccn2c(Br)cnc12
Product: CNc1nccc(-c2cnc3c(NCCO)nccn23)n1

Procedure:
2-[3-(2-Methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-ethanol was prepared by a process analogous to that described in Example 12 starting from 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol (from Example 2 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and methylamine. LC-MS: [M+H]+ 286.2.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[N:14]=[N:15][C:11]=2[C:10]=1[C:22]([F:25])([F:24])[F:23])C1C=CC=CC=1.C(OCC)(=O)C>CO>[CH:17]1([CH2:16][N:13]2[C:12]3[CH:20]=[CH:21][C:9]([OH:8])=[C:10]([C:22]([F:24])([F:25])[F:23])[C:11]=3[N:15]=[N:14]2)[CH2:19][CH2:18]1
Reactant: FC(F)(F)c1c(OCc2ccccc2)ccc2c1nnn2CC1CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Reaction time: 1.5 h

Procedure:
5-Benzyloxy-1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazole (5.04 g, 14.5 mmol) was dissolved in 1:1 mixture of methanol: ethyl acetate (40 mL). The mixture was sparged under nitrogen, treated with Pearlman's catalyst (2 g, 0.2 wt equiv) and then sparged under hydrogen (1 atm) and stirred vigorously for 90 minutes. The mixture was filtered through a pad of Celite, which was washed with methanol (500 mL) and concentrated in vacuo, providing the titled compound
Reaction SMILES: Cl.COC(=O)[C@@H](CC1C=CC=CC=1)N.C[O:16][C:17](=[O:47])[C@@H:18]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:19][C:20]([CH2:22][C:23]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:26]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:25][CH:24]=1)=[O:21]>CO.C(OCC)(=O)C>[CH2:36]([C:26]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:23]([CH2:22][C:20]([NH:19][C@@H:18]([C:17]([OH:47])=[O:16])[CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:21])=[CH:24][N:25]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1ncc(CC(=O)N[C@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1ncc(CC(=O)N[C@H](Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
The procedure of Example 12 (ii-iii) was followed using D-phenylalanine methyl ester hydrochloride in place lycine methyl ester hydrochloride. The intermediate N-[{2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5 -yl}methylcarbonyl]-D-phenylalanine methyl ester was a solid; mp 179°-181° C. (from methanol/ethyl acetate). The title compound was a solid; mp 178°-181° C. (from methanol/ethyl acetate).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)[C:7]1=[O:34].Br[C:36]1[CH:41]=[CH:40]C=[CH:38][N:37]=1.C([O-])([O-])=O.[K+].[K+].C[N:49](C=O)C>C(Cl)Cl>[C:28]1([C:21]2([N:18]3[CH2:19][CH2:20][CH:15]([N:8]4[C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[N:6]([CH2:5][CH2:4][NH:3][C:38]5[N:37]=[CH:36][CH:41]=[CH:40][N:49]=5)[C:7]4=[O:34])[CH2:16][CH2:17]3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NCCn1c(=O)n(C2CCN(C3(c4ccccc4)CCCCCC3)CC2)c2ccccc21
Reactant: Brc1ccccn1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1n(CCNc2ncccn2)c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Yield: 8.6 %

Procedure:
A mixture of 1-(2-aminoethyl)-3-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride (37.81 mg, 0.0751 mmol, this was prepared according to the procedure of Preparation 18 and Example 64). 2-bromopyridine (14 mg, 0.0901 mol), K2CO3 (36 mg, 0.263 mmol), and DMF (1 ml) was stirred at 60° C. for 4 h. The mixture was diluted with CH2Cl2, washed with water, dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (acetone/hexane:2/3) to give 3.3 mg (8.6%) of colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[NH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[NH2:23][C:24]1[CH:29]=[C:28]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: Nc1cccc(B(O)O)c1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(N)c3)c(F)cn2c1=O
Yield: 24.6 %

Procedure:
Ethyl 8-(3-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (102.5 mg, 0.32 mmol) and (3-amino-phenyl)-boronic acid (54.8 mg, 0.40 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (30 mg, 25%). ESI-MS m/z: 381 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:9]1[C:13]([SH:14])=[N:12][N:11]=[N:10]1)[CH:7]=[CH2:8].[C:15](=[O:17])=[O:16].O>CCCCCC.O1CCCC1>[C:15]([CH2:8][CH:7]=[CH:6][N:9]1[C:13]([SH:14])=[N:12][N:11]=[N:10]1)([OH:17])=[O:16]
Reactant: O=C=O
Reactant: C=CCn1nnnc1S
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)CC=Cn1nnnc1S
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
15% solution of n-butyl lithium in hexane (371 ml) was dissolved in dry tetrahydrofuran (150 ml) and cooled to -20° C. To the solution was added dropwise a solution of 1-allyl-1H-tetrazole-5-thiol (38.7 g) in tetrahydrofuran (220 ml) with stirring under a stream of nitrogen gas during a period of 30 minutes. After the addition of solid carbon dioxide, the mixture was stirred for 30 minutes at -10° C. To the mixture was added water (275 ml) and then the resulting mixture was stirred. The aqueous layer was separated adjusted to pH 4.5, washed with ethyl acetate, adjusted to pH 3.8 to 4.0 and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated. The residue was washed with diisopropyl ether to give an oil of 1-(3-carboxy-1-propenyl)-1H-tetrazole-5-thiol (5.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([OH:37])(=O)=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:40])=O>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([Cl:40])(=[O:37])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(-c2c(S(=O)(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: Cc1c(-c2c(S(=O)(=O)Cl)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a suspension of the compound prepared in Example 191 (10.0 g) in acetonitrile (70 ml) was added phosphorus oxychloride (7.04 ml) and the resulting mixture was stirred at 90° C. for two hours. The mixture was concentrated on evaporator instrument under reduced pressure and to the residue were then added ethyl acetate (50 ml) and hexane (50 ml) and the mixture was stirred for thirty minutes. The precipitated solids were collected by filtration and washed with ethyl acetate/hexane=1/1 to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonylchloride (10.3 g). UPLC/MS 550 (M+H)/1.08 min. (measurement condition 9).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31]Br)[CH2:26][C@@H:25]2[CH3:34])=[C:20]([CH:35]=[CH:36][CH3:37])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C2C=C(C3(C)NC(=O)NC3=O)C=CC=2CC1.[O:55]1[C:64]2[C:59](=[N:60][CH:61]=[C:62]([C:65]3([CH3:72])[NH:69][C:68](=[O:70])[NH:67][C:66]3=[O:71])[CH:63]=2)[O:58][CH2:57][CH2:56]1>>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][N:67]3[C:66](=[O:71])[C:65]([C:62]4[CH:63]=[C:64]5[O:55][CH2:56][CH2:57][O:58][C:59]5=[N:60][CH:61]=4)([CH3:72])[NH:69][C:68]3=[O:70])[CH2:26][C@@H:25]2[CH3:34])=[C:20]([CH:35]=[CH:36][CH3:37])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cnc3c(c2)OCCO3)NC(=O)NC1=O
Reactant: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)C[C@@H]1C
Agent: CC1(c2ccc3c(c2)OCC3)NC(=O)NC1=O
Product: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3cnc4c(c3)OCCO4)C2=O)C[C@@H]1C

Procedure:
(S)-1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}-3-methylpiperazin-1-yl)-2-bromoethanone, 5-(2,3-dihydrobenzofuran-6-yl)-5-methylimidazolidine-2,4-dione and 5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Example 14-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH:1]1([N:7]([CH3:26])[C:8](=[O:25])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH:1]1([N:7]([CH3:26])[C:8](=[O:25])[C:9]2[CH:10]=[CH:11][C:12]([CH:15]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH3:27])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C(=O)c1ccc(Cn2cnc3ccccc32)cc1)C1CCCCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(c1ccc(C(=O)N(C)C2CCCCC2)cc1)n1cnc2ccccc21
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 11 %

Procedure:
To a stirred solution of N-cyclohexyl-N-methyl 4-(1H-benzimidazylmethyl)benzamide (347 mg, 1 mmol) in dry THF (20 ml) at -78 ° C. was added sodium bis(trimethylsilyl)amide (1.1 ml of 1M solution in THF) under argon. The mixture was left to stir at -78° C. for 40 minutes, a solution of methyl iodide (170 mg, 1.2 mmol) in dry THF (2 ml) was added and the mixture left to warm to ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and brine, the organic layer dried (Na2SO4), concentrated to give a crude product which was purified by column chromatography (flash silica gel, 4% methanol in DCM) to yield N-cyclohexyl-N-methyl 4-(1-(1H-benzimidazyl)ethyl)benzamide (40 mg, 11%) as a white crystalline solid.