Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH2:18][C:17](=[O:36])[NH:16][C:15]=2[CH:37]=1)(C)(C)C.C(OC(=O)NCCCC1C=CC2C3N=C(NC4C=CC(OC)=C(OC)C=4)N=CC=3CC(=O)NC=2C=1)(C)(C)C>>[NH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH2:18][C:17](=[O:36])[NH:16][C:15]=2[CH:37]=1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Agent: COc1ccc(Nc2ncc3c(n2)-c2ccc(CCCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(CCCN)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method P, {3-[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-9-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester (I-39) was converted to {3-[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-9-yl]-propyl}-carbamic acid tert-butyl ester (I-41: HRMS Calcd. for C28H33N5O5: 520.2559, found 520.2551), which was subsequently deprotected (Method K) to give I-50 (80%) HRMS Calcd. for C23H25N5O3: 420.2035, Found 420.2045.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC.C(OCC)(=O)C>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:27])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(c1ccc(Br)cc1)c1ccc(F)cc1F)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2F)ccc1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 5-(3-(4-bromophenyl)-3-(2,4-difluorophenyl)propanoyl)pyridin-2(1H)-one (0.225 g, 538 μmol) in N,N-dimethylacetamide (3 mL) was added potassium carbonate (81.8 mg, 592 μmol) and iodomethane (80.2 mg, 35.3 μL, 565 μmol) and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed twice with water and once with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Colourless foam (0.20 g, 86%). MS (ESI+): m/z=432.0 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:31][CH:30]=[CH:29][C:16]=3[N:17]=[C:18]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([Cl:27])=[CH:22][C:21]=3[F:28])[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1>CCOC(C)=O>[ClH:27].[ClH:32].[Cl:27][C:23]1[C:24]([F:26])=[CH:25][C:20]([C:18]2[N:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]3[S:31][CH:30]=[CH:29][C:16]=3[N:17]=2)=[C:21]([F:28])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1cc(-c2nc(N3CCNCC3)c3sccc3n2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.16 g of 1-tert-butoxycarbonyl-4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine and 10 ml of 4M HCl-dioxane solution was stirred for two days at room temperature. 10 ml of EtOAc was added to the reaction mixture. After the precipitate was filtered and washed with EtOAc, it was dried under reduced pressure to give 1.17 g of 2-(4-chloro-2,5-difluorophenyl)-4-piperazine-1-ylthieno[3,2-d]pyrimidine dihydrochloride.
Reaction SMILES: [CH2:1]([C:3]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:4]=1[C:5](N(OC)C)=[O:6])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C:3]1[C:4]([CH:5]=[O:6])=[CH:11][CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:14]=1)[CH3:2]
Reactant: CCc1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc(C(F)(F)F)ccc1C=O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a cooled (−78° C.) solution of 2-ethyl-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (113 mg, 0.43 mmol) in THF (4 mL) was added lithium aluminum hydride (1M LAH in THF, 0.22 mL). The mixture was stirred for 15 minutes, and then warmed to −10° C. After additional stirring for 30 minutes, the mixture was quenched with saturated potassium hydrogen sulfate solution (1 mL) and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 2-ethyl-6-trifluoromethyl-pyridine-3-carbaldehyde quantitatively as oil. The crude product was used directly in the following reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.CN([CH:17]=[O:18])C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:17]=[O:18])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(F)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (25 g) in toluene (142 mL) was added at −78° C. n-butyllithium (2.5M toluene solution, 68 mL), and the mixture was stirred at −78° C. for 1 hr. To this mixture was added at −78° C. DMF (16.5 mL), and the mixture was stirred at −78° C. for 2 hr, and saturated aqueous ammonium chloride solution (300 mL) was added. The mixture was extracted with ethyl acetate (300 mL), dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (20% ethyl acetate/hexane) to give 5-fluoropyridine-2-carbaldehyde (4.7 g, 26%) as a yellow oil.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:22]([C:33](=[O:35])[NH2:34])[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1)(=[NH:5])[NH2:4].CO[C:38]1[CH2:39][CH2:40][CH2:41][N:42]=1.N1CCCC1=O.C(N(CC)CC)C>C(O)C.Cl.O>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[CH2:14][N:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([C:38]4[CH2:39][CH2:40][CH2:41][N:42]=4)[CH2:29][CH2:28]3)=[C:22]([C:33](=[O:35])[NH2:34])[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1)(=[NH:4])[NH2:5]
Reactant: COC1=NCCC1
Reactant: CS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)c(C(N)=O)c1
Agent: Cl
Agent: O=C1CCCN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C3=NCCC3)CC2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.6 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-carbamoyl-4-(piperidin-4-yloxy)phenyl]methanesulfonamide dihydrochloride (0.95 g) obtained in example 99(a) in ethanol (15 ml) were added successively 5-methoxy-3,4-dihydro-2H-pyrrole (0.52 g), which was prepared from 2-pyrrolidinone according to the method described in Org. Prep. Proced. Int., 24, 147 (1992), and triethylamine (1.20 ml) at room temperature, and the resulting mixture was allowed to stand at room temperature overnight, and at the end of this time, 5-methoxy-3,4-dihydro-2H-pyrrole (0.17 g) and triethylamine (0.24 ml) were furthermore added successively, and the resulting mixture was stirred at room temperature for 6 hours and then evaporated in vacuo. Subsequently, to the residue obtained were added successively ethanol (10 ml) and a 4N solution of hydrogen chloride in dioxane (4 ml), and the resulting mixture was evaporated in vacuo. The residue obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 10% acetonitrile/water). The amorphous solid obtained was dissolved in 1N hydrochloric acid (5 ml), and the resulting mixture was evaporated to dryness in vacuo. The, residue obtained was dissolved in water and then lyophilized to afford the title compound (0.67 g, yield: 63%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].ON1C2C=CC=CC=2N=N1.CN(C)C=O.[NH2:39][C@@H:40]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH3:41]>ClCCl>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:39][C@@H:40]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH3:41])=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCCCC[C@@H](C)N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCC[C@@H](C)NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg), 1-hydroxybenzotriazole (23.7 mg), JANDAJEL-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (289 mg) and N,N-dimethylformamide (1 mL) were mixed together and the mixture was stirred at room temperature for 3 hours. Subsequently, (2R)-2-aminoheptane (46.6 μL) was added and the mixture was stirred at room temperature for 17 hours and 40 minutes. This was followed by addition of dichloromethane (0.5 mL) and (2R)-2-aminoheptane (11.6 μL), stirring at room temperature for 4.5 hours, addition of JANDAJEL-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (96.6 mg) and additional stirring at room temperature for 17 hours. Subsequently, (isocyanatomethyl)polystyrene (232 mg) was added and the mixture was stirred at room temperature for 2 hours. The insoluble material was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was then purified by silica gel column (eluant:ethyl acetate:methanol=10:1) to give (2S,4S)-4-fluoro-1-[[N-[4-[(2R)—N-(2-heptyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (9.0 mg).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:14])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[OH:15][C:16]1[CH:24]=[CH:23][C:19]2[CH2:20][CH2:21][O:22][C:18]=2[CH:17]=1>>[CH3:14][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:3][CH2:2][O:15][C:16]1[CH:24]=[CH:23][C:19]2[CH2:20][CH2:21][O:22][C:18]=2[CH:17]=1
Reactant: CC(=CCBr)CCC=C(C)CC(C)C
Reactant: Oc1ccc2c(c1)OCC2
Product: CC(=CCOc1ccc2c(c1)OCC2)CCC=C(C)CC(C)C

Procedure:
1-bromo-3,7,9-trimethyl-2,6-decadiene and 6-hydroxy-2,3-dihydrobenzofuran are reacted to form 6-[(3,7,9-trimethyl-2,6-decadienyl)-oxy]-2,3-dihydrobenzofuran of boiling point (bulb-tube) 112° C./0.03 mmHg; nD21 = 1.5271.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[C:20]3[CH:28]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36].C(NC(=O)C1C=CC=C(OC2C=CC(NC3C4C=C(N5CCCC5)N=CC=4N=CN=3)=CC=2C)C=1)(C)(C)C>>[C:35]([NH:39][C:9](=[O:10])[C:8]1[CH:7]=[CH:6][C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH:18][C:19]3[C:20]4[CH:28]=[C:27]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:17][C:2]=2[CH3:1])=[CH:13][CH:12]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1Oc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)N
Agent: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)NC(C)(C)C)c1
Product: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1Oc1ccc(C(=O)NC(C)(C)C)cc1

Procedure:
The title compound was prepared from 4-[2-Methyl-4-(6-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-benzoic acid and tert-butyl amine by a procedure analogous to the synthesis of N-tert-Butyl-3-[2-methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-benzamide. LRMS: 513.4 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.77 (s, 1H), δ 8.83 (s, 1H), δ 8.42 (s, 1H), δ 7.72-7.78 (m, 4H), δ 7.63 (s, 1H), δ 7.51 (s, 1H), δ 7.03 (d, J=9.14, 1H), δ 6.87 (d, J=8.72, 2H), δ 3.75-3.77 (m, 4H), δ 3.54-3.56 (m, 4H), δ 2.14 (s, 3H), δ 1.33 (s, 9H).
Reaction SMILES: [Li].C(OCC[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)C.[Cl:14][C:15]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:16]=1[CH:17]=O.Cl.C(=O)([O-])[O-].[K+].[K+]>CCOCC.C(O)C.[Pd].O.O1CCCC1>[Cl:14][C:15]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:16]=1[CH2:17][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:7]
Reactant: CCOCCOCCCCCBr
Reactant: COc1ccc(C=O)c(Cl)c1OC
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: COc1ccc(CCCCCCO)c(Cl)c1OC
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To 0.6 g (0.08 g-atoms) of lithium ribbon cut in small pieces in 40 mL of anhydrous ether stirred at room temperature under an argon atmosphere was added 9.5 g (0.04 mol) of 5-bromopentanol 2-ethoxyethyl ether. After about 1 mL was added, the reaction mixture was cooled to -5° and the rest of the bromo compound was added dropwise. Stirring at -5° was continued for 1 hour and then 6.0 g (0.03 mol) of 2-chloro-3,4-dimethoxybenzaldehyde [J. Weinstock et al., J. Med. Chem., 29, 2315 (1986)] in 50 mL of ether-20 mL of tetrahydrofuran was added dropwise over 1 hour. The cooling bath was removed and stirring was continued for 1 hour. The reaction mixture was worked up as in Example 10 to yield an oil which was dissolved in 25 mL of ethanol, 20 mL of water and 2 mL of concentrated hydrochloric acid was added. The solution was left at 25° for 45 minutes. Potassium carbonate was added with stirring until the mixture was basic. The ethanol was removed under reduced pressure and the product was extracted with ethyl acetate. The dried extract was concentrated to an oil (10 g). This was purified by HPLC using 60% ethyl acetate-hexane to give 2.9 g (34% yield), mp 75°-70°, of 6-(2-chloro-3,4-dimethoxybenzene)-6-hydroxyhexanol. This was dissolved in 50 mL of ethanol, 0.3 g of 10% palladium on carbon was added and the mixture was shaken under an initial hydrogen pressure of 54 psi for 21 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to an oil. Purification by HPLC using 15% ethyl acetate-toluene gave 1.74 g (64% yield) of 2-chloro-3,4-dimethoxybenzene hexanol as an oil. The structure was confirmed by nmr and mass spectra (molecular ion at m/e 272).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:25]=1.CC(C)([O-])C.[K+]>C1COCC1>[C:33]([O:32][C:30]([C:26]1[CH:25]=[C:24]([O:18][C@H:15]2[CH2:14][CH2:13][C@@H:12]([NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:19]([F:20])([F:21])[F:22])[CH:4]=3)=[O:10])[CH2:17][CH2:16]2)[CH:29]=[CH:28][N:27]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(O[C@H]2CC[C@@H](NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)CC2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-1-(4-chloro-3-trifluoromethyl-phenyl)-3-(4-hydroxy-cyclohexyl)-urea (0.38 g, 1.13 mmol) and tert-butyl 4-chloropicolinate (0.24 g, 1.13 mmol) in THF (12 mL) was added 1.0 M potassium tert-butoxide solution in THF (3.4 mL, 3.4 mmol) at 0° C. The reaction mixture was allowed to slowly warm to room temperature and then stirred overnight. The reaction was quenched by adding water and the resulting white precipitates were collected and washed with water. Purification by column chromatography (6:4 Hexanes-EtOAc) gave the title compound, 0.32 g (55%) as a yellowish powder. 1H NMR (300 MHz, DMSO-d δ 8.78 (s, 1H), 8.48 (d, J=6 Hz, 1H), 8.09-8.06 (m, 1H), 7.55-7.50 (m, 2H), 7.46 (d, J=2 Hz, 1H), 7.21 (dd, J=6 and 2 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 4.82-4.67 (m, 1H), 3.75-3.59 (m, 1H), 1.91-1.47 (m, 17H).
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-])=O)[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1>CO.[Pd]>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)[C:10]1[C:11]([NH2:20])=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1
Reactant: CN1CCC(N(C)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(N(C)c2ccc(C(F)(F)F)cc2N)CC1

Procedure:
To a solution of N,1-dimethyl-N-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-4-amine (11.3 g, 35.6 mmol) in MeOH (260 mL) at RT was added 10% Pd/C (1.89 g). H2 gas was bubbled through the solution for 5 minutes and the reaction was stirred under an atmosphere of H2 gas. The reaction was monitored by LCMS, and H2 gas was added periodically until consumption of starting material. The mixture was filtered through Celite® with MeOH and concentrated to afford the desired product.
Reaction SMILES: O=[C:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=1[O:19][CH3:20])[CH2:3][CH2:4][C:5]([O:7]C)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.C(O)(=O)C.[BH3-]C#N.[Na+].[OH-].[Na+]>C1COCC1.CO>[F:21][C:22]([F:32])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=3[O:19][CH3:20])[CH2:3][CH2:4][C:5]2=[O:7])=[CH:26][CH:25]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)CCC(=O)c1c(OC)cc(OC)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(OC)c(C2CCC(=O)N2Cc2ccc(OC(F)(F)F)cc2)c(OC)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 4-oxo-4-(2,4,6-trimethoxyphenyl)butanoate (200 mg; 0.70 mmol; 1.0 equiv.), (4-(trifluoromethoxy)phenyl)methanamine (677 mg; 3.54 mmol; 5.0 equiv.), acetic acid (472 mg; 7.86 mmol; 11.1 equiv.), and NaBH3CN (93 mg; 1.41 mmol; 2.0 equiv.) in anh. THF (1.5 ml), and anh. MeOH (1.5 ml) was refluxed, under nitrogen, for 24 h. After cooling to rt, 15% aq. NaOH was added, and the organic solvents were removed under reduced pressure. The residue was extracted with DCM, and the mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=50/1) afforded 1-(4-(trifluoromethoxy)benzyl)-5-(2,4,6-trimethoxyphenyl)pyrrolidin-2-one as a colorless oil. LC-MS (conditions D): tR=1.08 min.; [M+H]+: 425.72 g/mol.
Reaction SMILES: I[C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:11])[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([SH:29])[CH:18]=[C:19]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:20]=1>>[CH3:11][N:6]1[C:5]2[CH:12]=[CH:13][C:2]([S:29][C:17]3[CH:18]=[C:19]([C:21]4([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:20]=[C:15]([F:14])[CH:16]=3)=[CH:3][C:4]=2[N:8]([CH3:9])[C:7]1=[O:10]
Reactant: Cn1c(=O)n(C)c2cc(I)ccc21
Reactant: COC1(c2cc(F)cc(S)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)n(C)c(=O)n4C)c2)CCOCC1
Yield: 60 %

Procedure:
Using a similar procedure to that described in Example 1, 5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one was reacted with 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran to give 4-[3-(1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylthio)-5-fluorophenyl]-4-methoxytetrahydropyran in 60% yield, m.p. 128°-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CC(C)=O.[I-].[K+].CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5]#[N:6]
Reactant: ClCc1ccccc1
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 48 °C
Yield: 86.1 %

Procedure:
To a solution of 3-bromo-4-hydroxybenzonitrile (60 g, 303 mmol) in acetone (600 mL) under nitrogen, potassium carbonate (62.8 g, 455 mmol) was added followed by potassium iodide (0.503 g, 3.03 mmol). To the mixture benzyl chloride (49.3 mL, 424 mmol) was added dropwise and the mixture was heated at 50° C. (48° C. internal temp) for 16 h. Reaction mixture was cooled down to room temperature, taken up with water (500 mL)/Et2O (1 L). Phases were separated and the aqueous phase back extracted with Et2O (2×500 mL). Combined organics were washed with NaHCO3 saturated solution (400 mL), then with 1M HCl solution (400 mL) and brine. Crude solution was then dried over Na2SO4 and evaporated under reduced pressure to give crude material (110 g) as brown solid that was triturated with c-hex (500 mL) for 30 min. The solid was collected by filtration and washed with c-hex/EtOAc 9/1 (200 mL). Evaporation of residual solvents under high vacuum afforded title material (75.5 g; 261 mmol; 86%) as pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH2:12][C:11]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:15]2[CH2:16][CH2:17][C:11]3([O:10][N:9]=[C:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:12]3)[CH2:13][CH2:14]2)=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Clc1cccnc1C1=NOC2(CCNCC2)C1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(NC(=O)N2CCC3(CC2)CC(c2ncccc2Cl)=NO3)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 83 %

Procedure:
Compound K (0.130 g, 0.451 mmol) was dissolved in toluene (15 ml) and triethylamine (0.12 ml, 0.867 mmol) and 4-tert-butylphenyl isocyanate (0.08 ml, 0.451 mmol) were successively added. The reaction mixture was heated to boiling point and boiled under reflux for 3 h. After cooling of the reaction mixture to RT, the mixture was stirred for 36 h. The reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were washed with sat. Na2HCO3 solution (10 ml), dried over Na2SO4 and concentrated to dryness under vacuum. After purification of the residue by column chromatography (hexane:EtOAc1:1), the product was obtained in a yield of 83% (0.160 g).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([Cl:13])[CH:9]=[CH:8][CH:7]=2.[Cl-].[Al+3].[Cl-].[Cl-]>N1C=CC=CC=1>[CH3:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:13])[NH:5]1
Reactant: Cc1cc2c(Cl)cccc2[nH]1
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC1Cc2c(Cl)cccc2N1
Yield: 76.3 %

Procedure:
5 g of sodium borohydride was added to 66 ml of pyridine having dissolved therein 4.4 g of 2-methyl-4-chloroindole. To the mixture were added gradually 10.6 g of fine powders of aluminum chloride while ice-cooling with stirring. After completion of addition, the mixture was stirred and allowed to react at room temperature for 27 hours, the solvent was removed therefrom under reduced pressure. Water was added to the residue and the mixture was extracted with 100 ml of benzene. The benzene layer was washed with a saturated aqueous sodium chloride solution followed by concentrating. To the residue was added a 10% aqueous hydrochloric acid which caused foaming. After foaming ceased, the mixture was rendered neutral with an aqueous sodium carbonate solution followed by extracting the mixture with 100 ml of benzene. The benzene layer was dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the extract was purified through a silica gel column chromatography (eluant:chloroform) to obtain 3.4 g of 2-methyl-4-chloroindoline which was confirmed by NMR.