Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)C.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:18]=1[F:26].BrC1C=CC=CC=1F.[Li+].CC([N-]C(C)C)C.BrC1C(F)=C(C=CC=1)C=O.CC(C)([O-])C.[K+].BrC1C=CC=C(F)C=1F>C1COCC1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C(O)C.[Pt]=O.CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[CH2:4][C:22]3[C:17]([C:6]=2[C:7]=1[F:12])=[C:18]([F:26])[C:19]([CH2:23][CH2:24][CH3:25])=[CH:20][CH:21]=3
Reactant: CCCc1cccc(Br)c1F
Reactant: CCN(CC)C(=O)c1ccc(F)c(F)c1
Agent: O=[Pt]
Agent: CC(C)(C)[O-]
Agent: CC(C)[N-]C(C)C
Solvent: CCO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCc1ccc2c(c1F)-c1c(ccc(F)c1F)C2

Procedure:
Analogously to example 1, but using N,N-diethyl-3,4-difluorobenzamide (prepared from purchasable 3,4-difluorobenzoic acid [455-86-7] by successive reaction with thionyl chloride and diethylamine) instead of N,N-diethyl-4-n-propylbenzamide and 1-bromo-2-fluoro-3-propylbenzene (prepared from 1-bromo-2-fluorobenzene by lithiation with LDA in THF at −70° C. and subsequent reaction with DMF, Wittig reaction of the resulting 3-bromo-2-fluorobenzaldehyde with ethyltriphenylphosphonium bromide and potassium tert-butoxide in THF and hydrogenation with platinum oxide in ethanol) instead of 1-bromo-2,3-difluorobenzene, 3,4,5-trifluoro-6-propylfluorene is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.Cl.[CH3:30][NH:31][CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:31]([CH3:32])[CH3:30])=[O:24])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C[C@@H](c2ccc(C(=O)N(C)C)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 207, step 2, 4-[(S)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-benzoic acid (example 282, step 3) was coupled with dimethylamine hydrochloride using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white foam, MS (ESI+): m/z=421.1 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=O.[BH4-].[Na+].C(O)(=O)C.O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: O=C(CCCl)N1c2ccccc2CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: ClCCCN1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a solution of 3-chloro-1-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanone (14.0 g, 0.044 mol) in tetrahydrofuran (150 ml) at 0° C., sodium borohydride (6.66 g, 0.176 mol) was added, followed by dropwise addition of glacial acetic acid (10.0 ml). The resulting mixture was stirred at room temperature overnight and then heated at reflux temperature for 2 h. More sodium borohydride (6.50 g, 172 mmol) and then borontrifluoride diethyl etherate (20.0 ml, 0.163 mol) were added and heating at reflux temperature was continued for 20 h. Water (350 ml) was cautiously added and the phases were separated. The aqueous phase was extracted with toluene (3×100 ml). The combined organic phases were washed with brine (3×100 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (100 g) using a gradient of heptane and ethyl acetate (10:0→10:2), to give 4.58 g (38%) of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>ClCCl.C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Temperature: 25 °C

Procedure:
tert-Butyl [2-({1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]carbamate (2.5 g, 5.7 mmol) was dissolved in dichloromethane (30 mL) and 5N hydrochloric acid in isopropanol (20 mL) was added. After stirring over night at room temperature the solvent was evaporated in vacuo. Water (30 mL) was added and the aqueous phase was neutralized with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product (1.76 g) was used without purification for the next step.
Reaction SMILES: CN(CCO)C.[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[CH:18]=[N:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][C:14]2=[O:25])=[CH:10][CH:9]=1.Br[C:29]1[S:30][C:31]([Cl:34])=[CH:32][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu].[Cu]I.C(OCC)(=O)C.CCOCC.O>[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[CH:18]=[N:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:29]4[S:30][C:31]([Cl:34])=[CH:32][CH:33]=4)[CH2:21][CH2:20]3)=[N:15][C:14]2=[O:25])=[CH:10][CH:9]=1
Reactant: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Reactant: Clc1ccc(Br)s1
Agent: [Cu]
Agent: [Cu]I
Agent: CN(C)CCO
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: O=c1nc(N2CCN(c3ccc(Cl)s3)CC2)ncn1Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 1.2 %

Procedure:
An N,N-dimethylaminoethanol suspension (1 mL) of 1-(4-chlorobenzyl)-4-(piperazin-1-yl)-1,3,5-triazin-2(1H)-one (30 mg, 0.10 mmol) synthesized in Reference Synthesis Example 9, 2-bromo-5-chlorothiophene (110 μL, 0.10 mmol), copper (3.0 mg, 0.05 mmol), copper (I) iodide (9 mg, 0.05 mmol), and potassium phosphate (43 mg, 0.20 mmol) was stirred at 80° C. for 3 days. After the completion of the reaction, water was added to the reaction solution and extraction with ether and ethyl acetate from the resultant reaction solution was performed. The organic layer was washed with brine, was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (0.5 mg, yield: 1.2%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(Cl)cc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Cl)cc(Cl)c1Cl
Reaction time: 3.5 h

Procedure:
To a solution of 2,3,5-trichlorobenzaldehyde (Aldrich, 50 gms) in ethanol (1.0L) at room temperature was added NaBH4 (7.00 gms) and the resulting mixture stirred for 3.5 hours. The reaction was quenched with water, and the solvent evaporated in vacuo before partitioning the residue between CHCl3 and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo to leave a white solid. 43.00 gms, mp. 90°-93° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4](O)[CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[C:11]([N+:18]([O-])=O)[CH:10]=1>>[CH3:8][C:9]1[CH:10]=[C:11]([NH2:18])[C:12]2[CH:13]=[CH:14][N:15]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:16]=2[CH:17]=1
Reactant: Cc1cc([N+](=O)[O-])c2cc[nH]c2c1
Reactant: OC1CCOCC1
Product: Cc1cc(N)c2ccn(C3CCOCC3)c2c1

Procedure:
In accordance with Example 68 (Steps 1 and 2), tetrahydro-2H-pyran-4-ol was used instead of (S)-tetrahydrofuran-3-ol, and 6-methyl-4-nitro-1H-indole was used instead of 4-nitro-1H-indole to obtain 6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indol-4-amine.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.O.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C1CCCCC1>[C:24]1([CH:23]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: C(=Nc1c2c(nc3ccccc13)CCCC2)c1ccccc1

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was dissolved in 400 ml of warm toluene and then morpholine (3.5 g) and benzaldehyde1 (2.65 g) were added and the reaction mixture was brought to reflux with a Dean-Stark water separator. After the solution was refluxed overnight an additional 2.65 g of benzaldehyde was added and reflux was continued an additional five (5) hours. At the end of this time the volatiles were removed under reduced pressure and the residue was purified by flash chromatography (EtOAc) to give 3.18 g of pure porduct after trituration with Et2O. Analytically pure material was obtained by recrystallization from cyclohexane, m.p. 168°-169° C.
Reaction SMILES: C[S:2]([C:4]1[CH:9]=[C:8]([C:10]2[S:14][C:13](CCCCC)=[CH:12][CH:11]=2)[C:7]([S:20](C)=O)=[CH:6][C:5]=1[C:23]1[S:27][C:26](CCCCC)=[CH:25][CH:24]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.FC(F)(F)S(O)(=O)=O>>[S:14]1[C:10]2[C:8]3[CH:9]=[C:4]4[S:2][C:24]5[CH:25]=[CH:26][S:27][C:23]=5[C:5]4=[CH:6][C:7]=3[S:20][C:11]=2[CH:12]=[CH:13]1
Reactant: CCCCCc1ccc(-c2cc(S(C)=O)c(-c3ccc(CCCCC)s3)cc2S(C)=O)s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)C(F)(F)F
Product: c1cc2sc3cc4c(cc3c2s1)sc1ccsc14
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottomed flask was filled with 5,5′-(2,5-bis(methylsulfinyl)-1,4-phenylene)bis(2-pentylthiophene) (2a) (885 mg, 1.7 mmol), phosphorus pentoxide (93 mg, 0.658 mmol) and trifluoromethanesulfonic acid (20 ml). The mixture was stirred for 72 h at room temperature to give a dark brown solution, which was then poured into ice-water (100 ml). The yellow precipitate was collected by suction filtration and dried under vacuum. The structure of this compound, which was insoluble in apolar organic solvents, was assumed to be the sulfonium salt. Demethylation of the solid was achieved by refluxing it in pyridine (132 ml) for 12 h. When the suspension was cooled to room temperature, a large volume of CH2Cl2 was added to extract the product. Dithieno[2,3-d:2′,3′-d′]benzo[1,2-b:4,5-b′]dithiophene (1a) was thus obtained as off-white powder by Hexane as an eluent and recrystalise in dichloromethane (200 mg, 26%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:47])[CH2:10][CH2:11][N:12]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:43]COC)=[C:19]([CH:42]=1)[C:20]([NH:22][C:23]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH3:13]>>[CH3:8][N:9]([CH3:47])[CH2:10][CH2:11][N:12]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:43])=[C:19]([CH:42]=1)[C:20]([NH:22][C:23]1[CH:35]=[C:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:33]=[CH:32][C:24]=1[C:25]([OH:27])=[O:26])=[O:21])[CH3:13]
Reactant: COCOc1ccc(CN(C)CCN(C)C)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCN(C)Cc1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
Trifluoroacetic acid (5.0 mL) was added to the obtained tert-butyl 2-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate (0.070 g), followed by stirring at room temperature for 8 hours. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the residue. After adjusting the pH to 6.3 with a saturated aqueous solution of sodium bicarbonate, the organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.045 g of 2-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:13][C@H:14]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[F:1][C:2]1[CH:3]=[C:4]([S:9]([NH:13][C@H:14]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(=O)(=O)c3ccc(F)c(F)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 3,4-difluorobenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 556.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[C:12]1[CH:13]=[N:14][N:15](CC2CCNCC2)[CH:16]=1.[OH-].[Na+]>CO.O>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]3[CH:16]=[N:15][NH:14][CH:13]=3)=[CH:6][NH:7]2)=[CH:3][CH:2]=1
Reactant: Fc1cc2[nH]cc(-c3cnn(CC4CCNCC4)c3)c2cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc2c(-c3cn[nH]c3)c[nH]c2c1
Temperature: 85 °C
Reaction time: 4 h
Yield: 35.9 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 183 mg; 0.54 mmol) in MeOH (20 mL) was added a solution of NaOH (142 mg; 3.55 mmol) in water (1 mL). The reaction mixture was stirred at 85° C. for 4 h, concentrated, diluted with H2O (5 mL), and extracted with Et2O (10 mL×3). The combined organic layers were washed with water (10 mL×2), brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC. 39 mg (36%) of the title compound was obtained as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:47]=[CH:46][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][N:33](C(OCC6C=CC=CC=6)=O)[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:48][CH3:49])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:47]=[CH:46][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:48][CH3:49])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)NN2CCN(C(=O)OCc3ccccc3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C(=O)NN2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 92.5 %

Procedure:
Benzyl 4-(4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)piperazine-1-carboxylate (850 mg, 1.25 mmols) was dissolved in ethanol (15 mL), added 10% Pd—C (170 mg, 20% wt) under inert atmosphere and hydrogenated using a balloon for 8 hrs. Then filtered the solution through celite bed and evaporated to give the product (630 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.89 (m, 10H) 2.70-2.85 (m, 8H) 3.31 (s, 3H) 3.93 (s, 3H) 4.06 (t, J=13.26 Hz, 2H) 4.46 (m, 1H) 7.42 (d, J=8.0 Hz, 1H) 7.44 (s, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.26 (d, J=8.08 Hz, 1H) 9.38 (s, 1H). [M+H] calculated for C26H34F2N8O3, 545. found 545.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:15][C@@H:16]1[CH2:18][O:17]1>C(O)C>[O:17]1[CH2:18][C@@H:16]1[CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClC[C@@H]1CO1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C[C@H]2CO2)CC1
Reaction time: 12 h
Yield: 94.9 %

Procedure:
Tert-butyl piperazine-1-carboxylate 7a (7.44 g, 40 mmol) and (S)-2-chloromethyl-oxirane (3.70 g, 40 mmol) were dissolved in 60 mL of ethanol. The reaction solution was stirred for 12 hours. The resulting solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[[(2S)-oxiran-2-yl]methyl]piperazine-1-carboxylate 20a (9.20 g, yield: 95.0%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:19])[CH2:9][C:10]2[NH:14][C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([C:9]1[CH:25]=[CH:24][C:23](=[O:26])[N:14]2[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[NH:11][C:10]=12)=[O:19]
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cccc(Br)c1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1cccc(Br)c1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 232.4 mg (0.73 mmol) of 1-(3-bromophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXVIII), 78.7 mg (1.46 mmol) of sodium methylate and 61.2 mg (0.73 mmol) methyl propiolate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].C(O)C.[H-].[Na+].Cl.[C:24](=O)([O:28]CC)[O:25][CH2:26][CH3:27]>O>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:24]([O:25][CH2:26][CH3:27])=[O:28])=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-benzyloxyacetophenone (36 g, 159 mmol) in diethyl carbonate (200 ml) was added ethanol (0.6 ml) and sodium hydride (60% in oil, 12.7 g, 318 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 2 hrs. To the reaction solution was added 6N hydrochloric acid to stop the reaction, and water (500 ml) was added. Then, the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the objective substance (49.3 g, 100%).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Reactant: NCc1cccc(Br)c1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1cccc(Br)c1
Temperature: 130 °C
Yield: 105.9 %

Procedure:
To a mixture of 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (3.6 g, 12 mmol) and 3-bromobenzyl amine (2 mL, 15 mmol) in DMA (50 mL) was added DIPEA (6 mL, 35 mmol) and heated to 130° C. for 16 h. The mixture was cooled to RT and poured into water (400 mL). The resulting orange/red suspension was extracted with EtOAc and the combined organics were washed with water and brine. The organic layer was concentrated to dryness to afford 5.9 g of a solid that was used without further purification. MS (ESI): mass calcd. for C23H18BrN3O3, 464.32; m/z found 465.0 [M+H]+. 1H NMR (400 MHz; CDCl3) δ 8.32-8.27 (m, 1H), 8.20 (d, J=8.3, 1H), 8.09 (d, J=8.3, 1H), 7.86 (d, J=3.0, 1H), 7.85-7.81 (m, 1H), 7.77-7.71 (m, 1H), 7.63 (d, J=8.3, 1H), 7.58-7.53 (m, 1H), 7.48 (s, 1H), 7.44-7.40 (m, 1H), 7.28-7.20 (m, 3H), 6.71 (d, J=9.3, 1H), 5.33 (s, 2H), 4.51 (d, J=5.8, 2H).
Reaction SMILES: [CH3:1][O:2][NH2:3].C(N(CC)CC)C.[O:11]=[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]([N:22]=[C:23]=[O:24])[CH2:14][CH2:13]1>C(Cl)Cl>[CH3:1][O:2][NH:3][C:23]([NH:22][CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:11])[CH2:13][CH2:14]1)=[O:24]
Reactant: O=C=NC1CCC(=O)c2ccccc21
Reactant: CON
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)NC1CCC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-methoxyamine (2.5 g), triethylamine (3.04 g) and dry methylene chloride (50 ml) is stirred at room temperature for 20 minutes under a nitrogen atmosphere. Then a solution of 1,2,3,4-tetrahydro-4-oxo-1-naphthyl isocyanate (5.62 g) in dry methylene chloride (50 ml) is added dropwise. After stirring at room temperature for 40 minutes, the reaction mixture is evaporated to dryness in vacuo and the solid residue washed with water (3 × 150 ml) to yield 6.1 g. title product, m.p. 148° to 151° C. Recrystallization from benzene affords crystals, m.p. 155° to 158° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].[I:14]([O-])(=O)=O.[K+].II.Cl>C(O)C.O>[OH:1][C:2]1[C:7]([I:14])=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)C(=O)c1ccc(O)cc1O
Reactant: [O-][I+2]([O-])[O-]
Agent: Cl
Agent: II
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)C(=O)c1ccc(O)c(I)c1O
Temperature: 25 °C
Yield: 558.3 %

Procedure:
Mechanically stir suspensions of 1-(2,4-dihydroxy-phenyl)-2-methyl-propan-1-one (818 g, 4.54 mol) in ethanol (3 L) and water (6 L) in two separate 22-L Morton flasks. Treat each suspension with potassium iodate (170 g, 794 mmol) and iodine (410 g, 1.62 mol) and allow to stir over night at room temperature. Dilute the mixtures with water (2 L), adjust pH to 4 by adding 5N hydrochloric acid, then extract twice with 4 L of ethyl acetate. Wash organic layers once with dilute aqueous sodium bisulfite, brine, dry with magnesium sulfate, filter, combine both filtrates, and evaporate to 2.6 Kg of a black solid. Chromatograph 500 g portions of the solid on 3.5 Kg of silica gel, eluting with 80% dichloromethane in heptane to provide the title compound (1357 g, 49% yield) in approximately 97% purity (HPLC shows 97% purity, with 3% 3,5-diiodo analog; LCMS confirms both. HPLC Rt=4.75 min; 1H NMR (CDCl3) δ 14.07 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.02 (s, 1H), 3.53 (hept, J=8.0 Hz, 1H), 1.24 (d, J=8.0 Hz, 6H); MS (m/z): 307.0 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH:16]1([NH2:20])[CH2:19][CH2:18][CH2:17]1>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:20][CH:16]1[CH2:19][CH2:18][CH2:17]1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: NC1CCC1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(OCCNC2CCC2)c1
Yield: 82.9 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and cyclobutylamine (1.17 ml, 13.46 mmol) in ethanol (4 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (400 mg, 82.7%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 202° C. MS m/z (relative intensity, 70 eV) 287 (M+, 0), 260 (33), 259 (91), 216 (bp), 215 (23), 56 (73).