Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH2:16][CH3:17])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:21])=O>O1CCCC1>[Cl:21][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH2:16][CH3:17])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)Nc1cccc(-c2ccc(=O)[nH]n2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 1.5 h

Procedure:
To a refluxing solution of 0.63 g of N-[3-(1,6-dihydro-6-oxo-3-pyridazinyl)phenyl]propanamide in 100 ml of dry tetrahydrofuran was added 0.5 ml of phosphorus oxychloride. After 1.5 hours, 0.5 ml of phosphorus oxychloride was added and after 2 hours of refluxing 0.25 ml of phosphorus oxychloride was added. The solution was refluxed for an additional hour, then the solvent was removed, dichloromethane was added and the solution was poured into ice water. The mixture was neutralized with sodium bicarbonate and extracted with dichloromethane. The extracts were combined, washed with water, dried and the solvent removed giving an oil. This oil was chromatographed on thick layer silica gel preparative plates with dichloromethane:methanol (95:5), as solvent to give 0.33 g of solid. Recrystallization of 0.15 g from dichloromethane-acetone-hexane gave the desired compound as white crystals, mp 188°-189° C.
Reaction SMILES: [C:1]([N:4]1[C@H:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][C:5]1=[O:16])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:26](/[CH:29]=[CH:30]/[C:31]1[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=1)[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:28])=[O:27]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N+:26]([CH2:29][C@@H:30]([C:31]1[CH:44]=[CH:43][CH:42]=[C:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=1)[CH2:2][C:1]([N:4]1[C@H:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][C:5]1=[O:16])=[O:3])([O-:28])=[O:27]
Reactant: O=[N+]([O-])/C=C/c1cccc(OCc2ccccc2)c1
Reactant: CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H](C[N+](=O)[O-])c1cccc(OCc2ccccc2)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
At −78° C., titanium(iv) chloride (1.0 M solution in DCM) (17.8 mL, 17.8 mmol) was added slowly to a solution of (R)-3-acetyl-4-benzyloxazolidin-2-one (available from Aldrich) (3.55 g, 16.2 mmol) in DCM (80 mL), followed by slow addition of diisopropylethyl amine (3.38 mL, 19.4 mmol). The mixture was stirred at −78° C. for 30 minutes and then a solution of (E)-1-((3-(2-nitrovinyl)phenoxy)methyl)benzene (94.1A) (4.13 g, 16.2 mmol) (commercially available from Aldrich) in DCM (17 mL) was added dropwise (over 15 minutes). Then TiCl4 (16 mL, 1.0 M solution in DCM) was added slowly to the reaction. The mixture was stirred at −78° C. for 2 hours and then quenched with NH4Cl solution. The mixture was extracted with EtOAc (350 mL) and the organic phase was washed with sodium bicarbonate solution and brine, dried over anhydrous Na2SO4. After removing solvent, the residue was recrystallized from MeOH, 94.1B (727 mg), white solid was obtained. MS ESI (np0s.) m/e: 475 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:18][OH:19])[C:11]=3[N:10]=[CH:9]2)C=CC=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1O>>[ClH:32].[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:19][CH2:18][CH:17]1[C:11]2[N:10]=[CH:9][NH:8][C:12]=2[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Oc1ccccc1Cl
Reactant: OCC1CCCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cl
Product: Clc1ccccc1OCC1CCCCc2[nH]cnc21

Procedure:
Using a procedure similar to that described in Example 22 and starting from (1-triphenylmethyl-1,4,5,6,7,8-hexahydrocycloheptaimidazole-4-yl)methanol (0.20 g, 0.49 mmol) and 2-chlorophenol (0.1 ml, 1 mmol) 94 mg (61%) of the title compound was obtained as a solid.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]O.O>O1CCOCC1.C(OCC)(=O)C>[Cl:5][C:6]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][Br:2]
Reactant: OCc1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: BrP(Br)Br
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc(Oc2ccccc2CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
Phosphorus(III) tribromide (0.41 ml, 4.37 mmol) was added to a solution of 1-[2-(2,4-dichlorophenoxy)phenyl]methanol (420 mg, 1.56 mmol) in dioxane (10 ml). The reaction mixture was stirred for 1 hour at room temperature. Another portion of phosphorus(III) tribromide (0.41 ml, 4.37 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. It was cooled to 0° C. Water (5 ml) was added dropwise. The reaction mixture was warmed to room temperature and diluted with ethyl acetate (400 ml). It was washed with a 10% aqueous solution of sodium hydrogensulphate. The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane 1:3 as eluent, to give 297 mg of 2-(2,4-dichlorophenoxy)benzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[CH2:11][O:12]C(C)=O>C(OCC)=O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:11]=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: NCc1ccc(F)cc1
Solvent: CCOC=O
Product: O=CNCc1ccc(F)cc1
Yield: 71 %

Procedure:
A solution of 4-fluorobenzylamine (20 g, 160 mmol) in ethyl formate was heated at reflux for 4 h. After cooling, the solvent was evaporated to afford a yellow solid. Trituration with cold EtOAc afforded the title compound as a white solid (17.46 g, 71%). 1H NMR (CDCl3): □8.24 (s, 1H), 7.25 (m, 2H), 7.00 (m, 2H), 5.91 (br s, 1H), 4.42 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:20])=[C:5]([C:15](OCC)=[O:16])[C:6](=[O:14])[C:7]2([CH3:13])[CH3:12].Cl.[C:22]([O:26][C:27](=[O:30])[CH2:28][NH2:29])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:20])=[C:5]([C:15]([NH:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[O:16])[C:6](=[O:14])[C:7]2([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2c(Cl)cccc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2c(Cl)cccc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
Ethyl 5-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (210 mg, 713 μmol, 1.0 eq) and glycine tert-butyl ester hydrochloride (143 mg, 855 μmol, 1.20 eq) were mixed in dioxane (5 mL) in a round bottom flask. DIPEA (186 μL, 1069 μmol, 1.5 eq) was added via syringe, and the reaction was stirred at 75° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude product was purified by silica flash chromatography (0-50% DCM/hexane) to give the desired compound as a white solid (204 mg). MS m/e=380 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH2:23][CH3:24])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH2:23][CH3:24])=[C:14]([Cl:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Product: CCOc1nc2c(cc1Cl)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 5, intermediate) (4R,9aR)-6-ethoxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-chlorosuccinimide.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([CH3:16])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1cncc(B(O)O)c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (600 mg, 2.419 mmol), 5-methylpyridine-3-boronic acid (348 mg, 2.54 mmol), PdCl2(PPh3)2 (170 mg, 0.242 mmol), sodium carbonate (769 mg, 7.26 mmol), 1,4-dioxane (6.5 mL), and water (1.6 mL) at 95° C. for 22 h. Purification by column chromatography (silica gel, 0-30% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(5-methylpyridin-3-yl)quinoline. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O1CCCCC1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>>[Cl:1][C:2]1[C:9]([F:10])=[C:8]([C:20]2[NH:19][N:18]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(I)c(F)c1Cl
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: N#Cc1ccc(-c2ccn[nH]2)c(F)c1Cl

Procedure:
The title compound was prepared from 2-chloro-3-fluoro-4-iodobenzonitrile (0.242 g, 0.86 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (0.239 g, 0.86 mmol) using the method of Example 34 (a) and (b). Yield 0.075 g. 1H NMR (400 MHz; MeOD): δ 6.84 (dd, 1H), 7.59 (m, 2H), 7.79 (s, 1H), 8.08 (bs, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.C(N([CH2:23][CH3:24])CC)C.[CH2:25]([Si:27](Cl)([CH2:30][CH3:31])[CH2:28][CH3:29])[CH3:26]>ClCCl>[CH2:25]([Si:27]([CH2:23][CH3:24])([CH2:28][CH3:29])[O:1][CH2:2][C:3]1([CH2:16][O:17][Si:27]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:25][CH3:26])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:26]
Reactant: CCN(CC)CC
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Reactant: CC[Si](Cl)(CC)CC
Solvent: ClCCl
Product: CC[Si](CC)(CC)OCC1(CO[Si](CC)(CC)CC)c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 87.1 %

Procedure:
1 g of 9,9-bis(hydroxymethyl)fluorene (4.4 mmol) was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, and 1.9 ml of triethyl amine (13.3 mmol) was added thereto. Then 1.85 ml of triethylsilyl chloride (11.1 mmmol) was added drop-wise, and the mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.75 g of concentrate (yield 87.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1.[CH2:30]([N:32](CC)CC)[CH3:31].C(N)C.O>CN(C)C=O.CO>[CH2:30]([NH:32][S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)(=[O:17])=[O:16])[CH3:31]
Reactant: CCN(CC)CC
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(=O)(=O)Cl)c3)nc(OC)n2)cc1
Agent: CCN
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCNS(=O)(=O)c1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonylchloride [0.065 g, Intermediate (10)] and triethylamine (0.25 mL) in dimethylformamide (3 mL) is cooled to 0° C. and the treated with a solution of ethylamine in MeOH (3 mL, 2 M). The mixture is allowed to reach room temperature overnight and poured into water (100 mL). This mixture is extracted twice with EtOAc (100 mL). The combined extracts are washed with water, dried over sodium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give N-ethyl-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonamide [20 mg, Example 4(b)]. MS: 443 (M+H), 1H NMR [(CD3)2SO]: δ 8.4 (1H, s); 8.2 (1H, m); 7.85 (1H, d, J=3 Hz); 7.75-7.8 (1H, m); 7.5-7.6 (2H, m); 7.2 (2H, d, J=7 Hz); 6.95 (2H, d, J=7 Hz); 6.6 (1H, s); 3.9 (3H, s); 3.7 (3H, s); 3.5-3.6 (2H, m); 2.8 (4H, m); 1 (3H, t). IC50=6.6 nM
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([O:18][CH:19]3[CH2:24][CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1.[H][H]>[Pd].[Ni].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([O:18][CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Fc1ccc(Cn2c(OC3CCN(Cc4ccccc4)CC3)nc3cncnc32)cc1
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(Cn2c(OC3CCNCC3)nc3cncnc32)cc1
Yield: 82.2 %

Procedure:
A mixture of 16.25 parts of 9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]oxy]-9H-purine and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with 3 parts of palladium-on-charcoal catalyst 10% and 6 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in trichloromethane and water was added. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was stirred in 1,1'-oxybisethane. The precipitated product was filtered off and dried, yielding 10.5 parts (82.2%) of 9-[(4-fluorophenyl)methyl]-8-(4-piperidinyloxy)-9H-purine; mp. 79.3° C. (compound 56).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH2:17])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH:17][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(CN)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCc1ccnc(CNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of 4-(t-butyloxycarbonylaminomethyl)-2-aminomethyl-pyridine(600 mg, 2.63 mmol), NMM (341 ml, 3.03 mmol), 4-DMAP (920 mg, 0.16 mmol) and benzyl chloroformate (433 ml, 3.30 mmol) in methylene chloride (15 ml) was stirred at room temperature overnight. The mixture was diluted with methylene chloride (50 ml) and then washed with water and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give an oil. The crude product was purified by MPLC using 70% ethyl acetate in hexane as eluting solvent to give the title compound 844 mg (100%).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][N:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[C:4]1([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)([Cl:31])=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:31][CH2:2][CH:3]1[CH2:7][N:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[C:4]1([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(c1ccccc1)N1CC(CO)C(c2ccccc2)(c2ccccc2)C1=O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(c1ccccc1)N1CC(CCl)C(c2ccccc2)(c2ccccc2)C1=O

Procedure:
To 34.0 g. (0.09 mole) of 4-(hydroxymethyl)-3,3-diphenyl-1-(1-phenylethyl)-2-pyrrolidinone in 200 ml. of chloroform was added 25.0 g. (0.20 mole) of thionylchloride. To this solution with stirring and ice bath cooling was added dropwise, 20.0 g. (0.26 mole) of dry pyridine maintaining the reaction mixture at 25° C. The solution was refluxed for 1.5 hours, concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed successively with dilute hydrochloric acid solution and dilute sodium hydroxide solution. The chloroform solution was dried, filtered, and concentrated in vacuo. The residue was dissolved in hot isopropyl ether and some isooctane was added. The hot solution was decanted from a gummy residue and the product crystallized from the cooled solution. Seven grams were recrystallized in isopropyl ether to give the product which melted at 115°-120° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[C:2]=[O:3].[CH3:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]3[CH:34]=[N:33][CH:32]=[N:31][C:27]=3[NH:28]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C1COCC1.CO>[CH3:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)=[O:3])=[CH:17][C:16]=1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]3[CH:34]=[N:33][CH:32]=[N:31][C:27]=3[NH:28]2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(N)cc1-c1ccc2c(c1)[nH]c1ncncc12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncncc12
Temperature: 25 °C

Procedure:
To 1-isocyanato-3-(trifluoromethyl)benzene (8.7 μl, 0.062 mmol) was added a solution of 4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)aniline (17.0 mg, 0.062 mmol) and DIPEA (16 μL, 0.089 mmol) in THF (0.4 mL). The reaction was stirred at ambient temperature until LCMS indicated complete reaction, typically 3-4 hours. The reaction mixture was diluted to a total of 2 mL with THF and MeOH and purified by preparative LCMS to recover the product as a TFA salt (16.7 mg, 46.9%). 1H NMR (400 MHz, CDCl3): δ 13.0 (bs, 1H), 9.65 (s, 1H), 9.15 (s, 2H), 8.93 (s, 1H), 8.37 (d, 1H), 8.01 (s, 1H), 7.4-7.6 (m, 5H), 7.2-7.4 (m, 3H), 2.21 (s, 3H). MS (EI) m/z=462 (M+H).
Reaction SMILES: CN(CC)C.[CH2:6]([N:13]1[CH2:35][CH2:34][N:16]2[C:17]3[CH:33]=[CH:32][CH:31]=[CH:30][C:18]=3[N:19]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=O)[CH2:20][CH2:21][CH:15]2[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[CH2:6]([N:13]1[CH2:35][CH2:34][N:16]2[C:17]3[CH:33]=[CH:32][CH:31]=[CH:30][C:18]=3[N:19]([CH2:22][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[CH2:20][CH2:21][CH:15]2[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1ccncc1)N1CCC2CN(Cc3ccccc3)CCN2c2ccccc21
Agent: CCN(C)C
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3c4ccccc4N(Cc4ccncc4)CCC3C2)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of alane-N,N-dimethylethylamine complex (Aldrich, 0.5 M in toluene, 3.1 mL, 1.55 mmol) was added dropwise with stirring to an ice-cooled solution of the product of Example 43 (123 mg, 0.309 mmol) in tetrahydrofuran (10 mL). The mixture was stirred under nitrogen as the ice bath was allowed to expire over 2.5 hours. The reaction was quenched by addition of methanol (2 mL) and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, eluted with CH2Cl2-methanol-15 MNH4OH) and then by HPLC (30×100 mm, C18, Waters XBridge™ column eluting with aqueous 0.1 M (NH4)2CO3-methanol (80:20-0:100 over 15 minutes)) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 1.60 (ddt, J=15.3, 2.4 Hz, 1H), 1.85-2.03 (m, 1H), 2.26 (t, J=10.7 Hz, 1H), 2.37 (td, J=11.1, 3.2 Hz, 1H), 2.70 (br d, J=10.7 Hz, 1H), 2.86-2.98 (m, 3H), 3.06 (dt, J=11.5, 2.8 Hz, 1H), 3.25-3.35 (m, 1H), 3.55 (td, J=11.4, 2.2 Hz, 1H), 3.61 (s, 2H), 4.32 (d, J=16.7 Hz, 1H), 4.61 (d, J=16.7 Hz, 1H), 6.75 (dd, J=6.8, 2.4 Hz, 1H), 6.78-6.92 (m, 2H), 6.94 (dd, J=7.1, 2.1 Hz, 1H), 7.24-7.39 (m, 5H), 7.42 (d, J=5.9 Hz, 2H), 8.40 (d, J/=6.3 Hz, 2H); MS (ESI) m/z 385 (M+H)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1.C(N(CC)CC)C.[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][C:46]=1[S:54](=[O:57])(=[O:56])[NH2:55].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49]([N:14]2[CH2:13][CH2:12][C:11]([C:6]3[CH:7]=[C:8]([F:10])[CH:9]=[C:4]([Cl:3])[CH:5]=3)([CH2:17][CH2:18][N:19]3[C@H:24]4[CH2:25][CH2:26][C@@H:20]3[CH2:21][CH:22]([N:27]3[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[N:29]=[C:28]3[CH3:36])[CH2:23]4)[CH2:16][CH2:15]2)=[O:50])=[CH:47][C:46]=1[S:54]([NH2:55])(=[O:57])=[O:56]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cc(F)cc(Cl)c2)CCNCC1
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cc(F)cc(Cl)c2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
A mixture of 1-((1R,5S)-8-{2-[4-(3-chloro-5-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.40 g, 0.78 mmol), triethylamine (0.35 mL, 2.5 mmol) and 4-chloro-3-sulfamoylbenzoic acid (184 mg, 0.78 mmol) in dimethylformamide (2.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (327 mg, 0.86 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by chromatography on silica gel eluting with a gradient of chloroform:methanol:ammonium hydroxide 400:15:1 to 200:15:1 to give 2-chloro-5-[(4-(3-chloro-5-fluoro phenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]benzenesulfonamide as a solid (0.20 g, 36%). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.67 (m, 1H), 7.60 (m, 1H), 7.51 (m, 1H), 7.42 (m, 1H) 7.30 (s, 1H), 7.10-7.21 (m, 4H), 4.72 (m, 1H), 4.06 (m, 1H), 3.57 (m, 1H), 3.47 (m, 1H), 3.30 (m, 3H), 2.52 (s, 3H), 2.40-2.48 (m, 4H), 2.27 (m, 1H), 2.14 (m, 1H), 1.83-2.04 (m, 10H), 1.70 (m, 2H). HRMS C35H38Cl2FN5O3S m/z 698.2134 (M+H)Cal., 698.2161 (M+H)Obs..