Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([CH2:16][CH2:17][CH3:18])[N:13]=[C:12]([NH:19][C:20](=[O:28])OC3C=CC=CC=3)[N:11]=2)[CH2:6][CH2:5]1>ClCCl>[CH3:1][N:2]([CH3:3])[C:20]([NH:19][C:12]1[N:11]=[C:10]([N:7]2[CH2:6][CH2:5][O:4][CH2:9][CH2:8]2)[N:15]=[C:14]([CH2:16][CH2:17][CH3:18])[N:13]=1)=[O:28]
Reactant: CNC
Reactant: CCCc1nc(NC(=O)Oc2ccccc2)nc(N2CCOCC2)n1
Solvent: ClCCl
Product: CCCc1nc(NC(=O)N(C)C)nc(N2CCOCC2)n1
Reaction time: 12 h
Yield: 39.9 %

Procedure:
A gaseous stream of dimethylamine is passed through a solution of 5 g (0.0145 mole) of phenyl (4-morpholino-6-propyl-1,3,5-triazin-2-yl)carbamate (compound 28 prepared in example 3) in 100 ml of anhydrous dichloromethane for three hours at a temperature of 20° C. The mixture is then allowed to stand for 12 hours. It is washed successively with a dilute sodium hydroxide solution and with water. The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue obtained crystallizes in a 50:50mixture (v/v) of ethyl acetate-hexane. 1.7 g of N,N-dimethyl-N'-(4-morpholino-6-propyl-1,3,5-triazin-2-yl)-urea is obtained.
Reaction SMILES: CN1CCNCC1.COCCO[Al-]OCCOC.[Na+].[C:20]([C:24]1[CH:28]=[C:27]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]([CH2:37][C:38]2[CH:47]=[CH:46][C:41]([C:42](OC)=[O:43])=[CH:40][CH:39]=2)[N:25]=1)([CH3:23])([CH3:22])[CH3:21].Cl>>[C:20]([C:24]1[CH:28]=[C:27]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]([CH2:37][C:38]2[CH:47]=[CH:46][C:41]([CH:42]=[O:43])=[CH:40][CH:39]=2)[N:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2CCc2ccccc2)cc1
Agent: CN1CCNCC1
Agent: COCCO[Al-]OCCOC
Agent: Cl
Product: CC(C)(C)c1cc(CCc2ccccc2)n(Cc2ccc(C=O)cc2)n1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
1-Methylpiperazine (10.7 g, 107 mmol) was added dropwise to sodium dihydridobis(2-methoxyethoxy)aluminate (70% toluene solution, 25 g, 86.6 mmol) at 0° C. To the obtained solution was added methyl 4-{[3-tert-butyl-5-(2-phenylethyl)-1H-pyrazol-1-yl]methyl}benzoate (1.65 g, 4.38 mmol) at 0° C. by small portions, and the mixture was further stirred at the same temperature for 1 hr. The reaction mixture was poured into 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.40 g, yield 92%) as a yellow oil.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C@@H:17]2[CH2:22][O:21][C@@H:20]([CH2:23][CH2:24][CH2:25][OH:26])[O:19][CH2:18]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.O>ClCCl>[CH3:4][S:1]([O:26][CH2:25][CH2:24][CH2:23][C@H:20]1[O:21][CH2:22][C@H:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([Cl:6])=[CH:8][CH:9]=2)[CH2:18][O:19]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC[C@H]1OC[C@H](c2ccc(Cl)c3ccccc32)CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCC[C@H]1OC[C@H](c2ccc(Cl)c3ccccc32)CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.256 g (2.23 mmol) of mesyl chloride in 2 ml of dichloromethane is added, dropwise, to a solution of 0.530 g (1.72 mmol) of trans-3-[5-(4-chloronaphthalen-1-yl)-1,3-dioxan-2-yl]-1-propanol prepared in step 5.1 and of 0.48 ml (3.45 mmol) of triethylamine in 8 ml of dichloromethane cooled to 0° C. under an inert atmosphere. The reaction mixture is stirred at 0° C. for 1 hour. 25 ml of water and 50 ml of dichloromethane are added. The mixture is separated off after settling out and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are washed with 25 ml of a saturated aqueous sodium chloride solution, drying is carried out over magnesium sulfate and concentration is carried out under vacuum, to obtain 0.66 g of product in the form of a white solid used without modification in the following step.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[K+]>CS(C)=O.O1CCCC1.C(OCC)C>[N:8]1[CH:9]=[CH:10][C:11]([O:14][N:20]2[CH2:21][CH2:22][CH2:17][CH2:18][CH2:19]2)=[CH:12][CH:13]=1
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1cc(ON2CCCCC2)ccn1
Reaction time: 16 h
Yield: 159.7 %

Procedure:
Part A: To a solution of N-BOC-4-hydroxypiperidine (3.00 g, 14.9 mmol) in dimethylsulfoxide (10 mL) are sequentially added 4-chloropyridine hydrochloride (2.35 g, 15.6 mmol) and potassium-t-butoxide (30.5 mL of a 1.0 M solution in tetrahydrofuran, 30.5 mmol). After 16 hours at ambient temperature, the reaction mixture is diluted with diethyl ether (100 mL) and washed with water (3×) and brine, and then dried over sodium sulfate. Concentration of the organic solution gives the desired 4-pyridyloxypiperidine (4.24 g, 100%) as a white solid. Analytical calculation for C15H22N2O3: C, 64.73; H, 7.97; N, 10.06. Found: C, 64.48; H, 8.14; N, 9.82.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:21])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]([OH:7])=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[F:21][C:9]1[CH:8]=[C:4]([C:5]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:7])[CH:3]=[C:2]([F:1])[C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(CNc2c(F)cc(C(=O)O)cc2F)cc1
Reactant: C1COCCN1
Product: COc1ccc(CNc2c(F)cc(C(=O)N3CCOCC3)cc2F)cc1

Procedure:
Using 3,5-difluoro-4-(4-methoxy-benzylamino)-benzoic acid (95.4 mg) obtained in Step B in Example 1-D-24 and morpholine (33.8 μl) instead of 1-ethyl-piperazine, in the same manner as Step C in Example 1-D-24, the desired compound was obtained as a crude product (111 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@@H:15]([CH3:18])[CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[C@@H](C)CO>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: C[C@H](N)CO
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamide by substituting (R)-(−)-2-amino-1-propanol for (S)-(−)-2-amino-1-propanol HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.76 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.52 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.59 (m, 2H), 4.16 (m, 1H), 3.57 (m, 2H), 2.19 (s, 3H), 1.22 (d, 3H, J=6.0 Hz). ESHRMS m/z 508.0684 (M+H calculated for C22H21BrF2N3O4 requires 508.0678).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].Cl.CCOCC>C1COCC1>[ClH:1].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:10]1[CH2:11][CH2:12][C:7]2[NH:6][C:5]3[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=3[C:8]=2[CH2:9]1)=[O:28]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2.00 ml). 2-Chlorobenzoyl chloride (0.04 mL, 0.29 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 20 (47 mg, 51% yield) as a pale yellow solid. LC-MS (M+H=347, obsd.=347).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])=[CH:7][C:6]=1[CH:22]=[C:23]([Cl:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(#N)C>[CH3:1][N:2]([CH3:3])[C:15](=[O:16])[C:14]1[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=1[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[C:6]([CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[Cl:29])[CH:7]=1)=[O:21]
Reactant: CCOC(=O)C(Cl)=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Reactant: CNC
Solvent: CC#N
Product: CCOC(=O)C(Cl)=Cc1cc(NC(=O)C2=C(C(=O)N(C)C)CCCC2)ccc1Cl
Temperature: 22.5 °C
Reaction time: 20 h

Procedure:
1.39 ml of a 40% strength by weight aqueous dimethylamine solution were added to a solution of 3.9 g of N-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)phenyl]-3,4,5,6-tetrahydrophthalimide in 100 ml of acetonitrile at about 20° C. The mixture obtained was stirred for a further 20 hours at 20-25° C., after which the solid formed was separated off, washed with petroleum ether and finally dried. Mp.: 161-164° C.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH3:20])[NH:6][C:7]=1[C:8]1[C:9]([CH3:19])=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[N:4]=[C:5]([CH3:20])[NH:6][C:7]=1[C:8]1[C:9]([CH3:19])=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(-c2[nH]c(C)nc2C=O)c(C)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2[nH]c(C)nc2CO)c(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 5-(4-formyl-2-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 236.2, 400 mg, 1.47 mmol) in methanol (20 mL). This was followed by the addition of NaBH4 (100 mg, 2.64 mmol) in several batches at 0° C. The reaction mixture was stirred for 1 h at room temperature, then was used for next step directly.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:20]([N:23]=[N+]=[N-])([O:21][CH3:22])[C:19](=[O:26])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].[H][H].C>O1CCOCC1.[Pt]=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:20]([NH2:23])([O:21][CH3:22])[C:19](=[O:26])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CO[C@@]1(N=[N+]=[N-])C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21
Agent: O=[Pt]
Solvent: C1COCCO1
Product: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21

Procedure:
A solution of t-butyl (6R,7R and S[5:1])-3-acetoxymethyl-7-azido-7-bromoceph-3-em-4-carboxylate (17.255 g, 39.8 mmole), pyridine (3.24 ml, 40 mmole), silver tetrafluoroborate (8.55 g, 43.8 mmole) in methylene chloride (160 ml), and methanol (320 ml) was stirred at +20° to +25° for 16 hours (a grey precipitate appeared within 1 to 2 minutes, but t.l.c. indicated that the long reaction-time was necessary). The mixture was filtered through Celite and the filtrate was evaporated and chromatographed on silica gel (250 g) in 5% ethyl acetate in benzene. A mixture of t-butyl (6R,7R and S[1:5])-3-acetoxymethyl-7-azido-7-methoxyceph-3-em-4-carboxylates was obtained as a pale-yellow viscous oil which slowly crystallised (13.910 g, 36.2 mmole, 90.5%), λmax 248.5 nm, inflexion at 265 nm (ε7,500 and 7,060 respectively). The n.m.r. spectrum indicated the assigned isomer ratio. Crystallisation of a sample from ether and petroleum-ether (b.p. 60° to 80°) provided a sample of t-butyl(6R,7S)-3-acetoxymethyl-7-azido-7-methoxyceph-3-em-4-carboxylate as a white crystalline solid m.p. 77.5° to 78.5°(dec); [α]D -33.2°; t.l.c. Rf 0.51: λmax 247.5 nm, inflexion at 264.5 nm (ε 8,180 and 7,600 respectively). c)(i) A suspension of platinum oxide (99.4 mg) in dry dioxan (10 ml) was stirred under a dry nitrogen atmosphere. A slow stream of hydrogen was then bubbled through the suspension for 3 minutes. A solution of t-butyl (6R,7S)-3-acetoxymethyl-7-azido-7-methoxyceph3-em-4-carboxylate (98.7 mg, 0.257 mmole) in dry dioxan (5 ml) was added to the suspension and stirring continued for a total of 25 hours; the stream of hydrogen was passed for the first 71/2 hours and the last 2 hours of this period. The black solution-suspension was stirred with charcoal (2 g) for 10 minutes and then filtered through a bed of charcoal on kieselgel G (Merck) on Celite. The filtrate was evaporated to give a crude sample of the title compound, t.l.c. Rf 0.13.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH3:21][C:22](=O)[CH2:23][C:24](=[O:26])[CH3:25]>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:21][C:22]1[N:1]=[C:2]2[S:3][C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:5][C:6]2=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:23]=1[C:24](=[O:26])[CH3:25]
Reactant: Nc1sc(-c2ccccc2)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc(-c3ccccc3)cc2c1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
To a stirred solution of 55 mg (0.197 mmol) (2-amino-5-phenyl-thiophen-3-yl)-phenyl-methanone-in-5 ml-acetic acid was added 0.016 ml (0.239 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 19 mg (28%) 1-(6-methyl-2,4-diphenyl-thieno[2,3-b]pyridin-5-yl)-ethanone as a light grey solid. ES-MS m/e (%): 344 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][CH:18]([CH3:26])[CH2:19][C:20](=O)[CH2:21][C:22](=[O:24])[CH3:23]>>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:20]([CH2:19][CH:18]([CH3:26])[CH3:17])[C:21]([C:22](=[O:24])[CH3:23])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)CC(C)C
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: CC(=O)c1c(CC(C)C)nc2ccc(Br)cc2c1-c1ccccc1
Yield: 9 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 6-methyl-2,4-heptanedione according to the procedure of example 1. Yield: 9%. MS: m/z=381 (M).
Reaction SMILES: N12CCCN=C1CCCCC2.CS(O[CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)=[C:26]([F:36])[CH:25]=2)[CH2:19]1)(=O)=O.CS(Cl)(=O)=O.[SH:42][C:43]1[NH:44][CH:45]=[CH:46][N:47]=1>O1CCOCC1>[NH:44]1[CH:45]=[CH:46][N:47]=[C:43]1[S:42][CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][O:33][CH2:34][CH:35]=3)=[C:26]([F:36])[CH:25]=2)[CH2:19]1
Reactant: Sc1ncc[nH]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: O=C1O[C@@H](CSc2ncc[nH]2)CN1c1ccc(C2=CCOCC2)c(F)c1
Temperature: 60 °C
Yield: 30 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.1 ml, 0.674 mmol) was added to a stirred suspension of 5(R)-methanesulfonyloxymethyl 3-(4-[3,6-dihydro-(2H)-pyran-4-yl]-3-fluorophenyl)oxazolidin-2-one (prepared from the 5(R)-hydroxymethyl compound (WO97/09328) by reaction with methylsulfonyl chloride) (0.25 g, 0.674 mmol) and 2-mercaptoimidazole (0.067 g, 0.674 mmol) in dioxan (2 ml) under nitrogen. The mixture was heated at 60° C. for 4 hours and evaporated. The residue was purified by column chromatography, eluting first with 2% MeOH/EtOAc and then with 4% MeOH/EtOAc to give the title product as a solid (0.077 g, 30%); mp 178-179° C. (dec.) MS: 476 (MH+); NMR: 2.39 (2H, bs); 3.42 (2H, m); 3.79 (2H, t); 3.86 (1H, m); 4.19 (3H, m); 4.89 (1H, m); 6.07 (1H, s); 7.04 (2H, s); 7.26 (1H, dd); 7.38 (1H, t); 7.46 (1H, d).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C1C(=O)N([Br:27])C(=O)C1>C(#N)C>[Br:27][C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1sccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC#N
Product: Cc1sc(Br)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of Compound 1059 (810 mg; 2.89 mmol) in 15 mL of acetonitrile was added NBS portionwise (505 mg; 2.83 mmol). The reaction mixture was stirred at room temperature for 10 minutes, quenched with saturated Na2SO3 solution, and extracted with EtOAc (3×). The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo to give a crude light yellow semi-solid. The residue was purified by medium pressure silica gel chromatography, eluting with 0-20% EtOAc/hexanes over 25 minutes, to give tert-butyl 4-(5-bromo-2-methylthiophen-3-yl)piperidine-1-carboxylate (Compound 1060, 590 mg, 57%); 1H NMR (CDCl3): δ 6.7 (s, 1H), 4.2 (m, 2H), 2.6 (m, 3H), 2.2 (s, 3H), 1.6 (m, 2H), 1.5 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:17]([CH3:21])([CH3:20])[C:18]#[CH:19]>CN(C)C=O>[CH3:20][C:17]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([C:18]#[CH:19])[CH3:21]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C#CC(C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(C)n1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a stirred solution of carbazole (2.500 g, 15.0 mmol) in anhydrous N,N-dimethylformamide (30 mL) at 0° C. was added 60% sodium hydride in mineral oil (0.718 g, 17.9 mmol) and the mixture was stirred at 0° C. for 1 hr. 3-Chloro-3-methyl-1-butyne (2.300 g, 22.4 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hr and then slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-70% methylene chloride/hexanes) to afford the desired product as a light brown solid (1.7 g, 49%). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, 2H, J=7.5 Hz), 8.04 (d, 2H, J=8.7 Hz), 7.41 (td, 2H, J=8.1, 1.5 Hz), 7.24 (t, 2H, J=7.5 Hz), 2.67 (s, 1H), 2.28 (s, 6H).
Reaction SMILES: [Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[N:8]1[CH2:17][CH2:16][N+:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1.[Cl:18][C:19]1[N:20]=[C:21]([CH3:25])[NH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][C:19]1[N:20]=[C:21]([CH3:25])[N:22]([CH2:12][CH2:13][CH2:14][CH2:15][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[N:2]=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:17][CH2:16]2)[C:23]=1[Cl:24]
Reactant: Cc1nc(Cl)c(Cl)[nH]1
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncccn2)CC1

Procedure:
A mixture of 450 g (1.5 moles) of 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide, 225 g (1.5 moles) of 4.5-dichloro-2-methylimidazole and 300 g (2.25 moles) of potassium carbonate in 2 l of dimethylformamide is heated to 130°-135° for 14 hours. The mixture is evaporated under vacuum, chloroform is added, the solution is washed with water, dried over sodium sulfate and evaporated under vacuum, and 503 g (91%) of 4,5-dichloro-2-methyl-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-imidazole are obtained in liquid form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27]C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][CH2:25][OH:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[ClH:1].[NH2:27][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][CH2:25][OH:26])[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2CCO)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2CCO)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step e) using N-((1R)-1-[(4-chlorophenyl)methyl]-2-(4-[2-(hydroxyethyl)phenyl]piperidyl)-2-oxoethyl)(tert-butoxy)carboxamide (Step d) (0.976 g, 2.0 mmol) and satd anhydrous HCl in EtOAc (30 mL). The title compound was obtained as a white solid (0.846 g). MS (ESI, pos. ion) m/z: 387 (M+1) MS (EST, neg. ion) m/z: 385 (M−1). Calc'd for C22H27ClN2O2: 386.18.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].Cl.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1.CCOCC>[F:28][C:26]([F:27])([F:29])[C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([C:2]([F:31])([F:30])[F:1])[CH:25]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1-c1cnccc1C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cnccc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a solution of 0.26 g (0.59 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-3-o-tolyl-isonicotinamide in 5 ml tetrahydrofuran 3.6 ml of a 1M solution of BH3 in tetrahydrofuran was added and the reaction mixture stirred for 16 h at 60°. After addition of 5 ml 3M HCl in ether the reaction mixture was stirred for 3 h at 60° C. The solution was cooled to room temperature and 10 ml 3N sodium hydroxide solution and 10 ml ethyl acetate were added. Stirring was continued for ½ h, the phases separated and the aqueous phase extracted twice with 15 ml ethyl acatate. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.13 g (51%) of the title compound as a pale yellow oil.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:15]2=[O:31])=[CH:9][C:8]=1[CH3:32])(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:46][CH2:47][CH2:48][O:49][Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:10]2[CH:11]=[C:12]([CH3:13])[C:7]([OH:6])=[C:8]([CH3:32])[CH:9]=2)([CH2:46][CH2:47][CH2:48][OH:49])[C:15]1=[O:31]
Reactant: Cc1cc(C2C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [F-]
Solvent: CN(C)C=O
Product: Cc1cc(C2(CCCO)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc(C)c1O
Yield: 50.3 %

Procedure:
Using a method similar to Example 37, with 3-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1-(2-chloro-benzyl)-1,3-dihydro-indol-2-one (150 mg, 0.31 mmol), a 0.5M solution of potassium bis(trimethylsilyl)amide (0.622 mL, 0.31 mmol), and (3-bromopropoxy)-tert-butyldimethylsilane (0.072 mL, 0.31 mmol) in DMF (3 mL) followed by treatment with TBAF (0.70 mL, 0.70 mmol) gives a crude brown gum. Purify by flash chromatography (gradient of 25% EtOAc/hexanes to 50% EtOAc/hexanes) to give 68 mg (51%) of the title compound as a pink solid. MS (ES): m/z=436 (M+1), 434 (M−1); 1H NMR(DMSO-d6): δ8.23 (s, 1H), 7.54 (dd, J=1.4 Hz, J=7.7 Hz, 1H), 7.37-7.22 (m, 4H), 7.12-7.04 (m, 2H), 6.90 (d, J=7.7 Hz, 1H), 6.83 (s, 2H), 5.05 (abq, J=16.7, 2H), 3.33 (m, under H2O), 2.27-2.18 (m, 2H), 2.11 (s, 6H), 1.23-0.99 (m, 2H).