Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([NH:27][C:28]3[N:37]=[CH:36][C:35]4[N:34]([CH3:38])[C:33](=[O:39])[C@@H:32]([CH2:40][CH3:41])[N:31]([CH:42]5[CH2:46][CH2:45][CH2:44][CH2:43]5)[C:30]=4[N:29]=3)=[C:22]3[O:26][CH2:25][CH2:24][C:23]=23)=[O:17])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:42]1([N:31]2[C:30]3[N:29]=[C:28]([NH:27][C:21]4[CH:20]=[CH:19][C:18]([C:16]([NH:15][CH2:14][CH:10]5[O:11][CH2:12][CH2:13][NH:8][CH2:9]5)=[O:17])=[C:23]5[C:22]=4[O:26][CH2:25][CH2:24]5)[N:37]=[CH:36][C:35]=3[N:34]([CH3:38])[C:33](=[O:39])[C@H:32]2[CH2:40][CH3:41])[CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: [H][H]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NCC4CN(Cc5ccccc5)CCO4)c4c3OCC4)nc2N1C1CCCC1
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NCC4CNCCO4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 101.4 %

Procedure:
N-[(4-benzylmorpholin-2-yl)methyl]-7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 2e (0.19 g, 0.30 mmol) was dissolved in 30 mL of methanol followed by the addition of palladium/carbon (40 mg, 10%), filled with hydrogen two times. The reaction solution was stirred for 2 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-(morpholin-2-ylmethyl)-2,3-dihydrobenzofuran-4-carboxamide 2f (163 mg) as a white solid, which was used in the next step without further furification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[N:5]=[C:4]([F:10])[C:3]=1Cl.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([F:10])[N:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Nc1c(F)c(F)nc(F)c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cc(F)nc(F)c1F
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A suspension of 4-amino-3-chloro-2,5,6-trifluoropyridine (2, 19.7 g, 108 mmol), 10% Pd/C (1.8 g) and triethylamine (20 mL, 140 mmol) in 150 mL of anhydrous ethanol was hydrogenated at 50 psi in a Parr hydrogenation apparatus until TLC showed the reaction was completed (about 18 hours). The catalyst was removed by filtration and carefully washed with ethanol. The combined filtrate and washings were evaporated to dryness in vacuo. The residue was stirred with 80 mL of water for 1 h, filtered, and washed with water to give 3 (14 g) as a white solid. The filtrate and washings were combined and extracted with ether. The combined ether layers were then dried (MgSO4) and concentrated to give an additional 1.3 g of 3 (total yield: 15.3 g, 96%). A small analytical sample was purified by silica gel column chromatography (Rf0.47, CH2Cl2): mp 94-96° C.; 1H NMR (CDCl3) δ4.78 (br s, 2 H, 4-NH2, D2O exchangeable), 6.20 (d, 1 H, 5-H). Analysis calculated for C5H3F3N2: C, 40.55; H, 2.04; N, 18.92. Found: C, 40.60; H, 2.16; N, 18.67.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH2:35][C:36]([OH:38])=O)[CH2:10]1)(=[O:8])=[O:7].[CH3:39][NH:40][CH3:41].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:39][N:40]([CH3:41])[C:36](=[O:38])[CH2:35][CH:30]1[CH2:31][O:32][CH2:33][CH2:34][N:29]1[CH2:28][C@H:11]1[CH2:10][N:9]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])[CH2:14][CH2:13][N:12]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCOCC2CC(=O)O)cc1)C(F)(F)F
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)CC1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
A 25-mL round-bottomed flask was charged with (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetic acid (65 mg, 0.113 mmol), dimethylamine (2.0 M in MeOH, 1.69 mL, 3.38 mmol, Sigma-Aldrich, St. Louis, Mo.), Hünig's base (0.039 mL, 0.225 mmol), HATU (471 mg, 1.24 mmol) and DMF (3 mL). After stirring at room temperature for 1 h, the reaction was concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 100% hexanes in EtOAc) to give N,N-dimethyl-2-(4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetamide (20 mg) as a mixture of four isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:26]1[CH:30]=[CH:29][CH2:28][CH2:27]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:23])[F:24])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:19][CH:27]3[CH2:28][CH2:29][CH2:30][O:26]3)=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(C(=O)NC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a solution of 0.25 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)benzoic acid amide that was synthesized under Synthetic Example 9 in 3 mL of dichloromethane, 68 mg of 2,3-dihydrofuran and a catalytic amount of p-toluenesulfonic acid monohydrate were added and the mixture was stirred for 18 hours at room temperature. The solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was purified using silica gel column chromatography that was eluted with ethyl acetate-hexane (2:3) followed by crystallization from a mixed solvent of hexane and a small amount of ethyl acetate to obtain 0.12 g of aimed product as yellow solid.
Reaction SMILES: C(O/[C:5](/[C:15]([O:17][CH3:18])=[O:16])=[C:6](/[O:11]C(=O)C)\[C:7]([O:9]C)=O)(=O)C.[NH2:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>CO>[CH3:18][O:17][C:15]([C:5]1[N:19]=[C:20]2[NH:24][CH:23]=[CH:22][N:21]2[C:7](=[O:9])[C:6]=1[OH:11])=[O:16]
Reactant: Nc1ncc[nH]1
Reactant: COC(=O)/C(OC(C)=O)=C(\OC(C)=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nc2[nH]ccn2c(=O)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 41 %

Procedure:
Dimethyl diacetoxyfumarate (3.2 g, 12 mmol), 2-amino imidazole (1.03 g, 12 mmol) and p-toluenesulphonic acid (395 mg, 2.0 mmol were mixed in a 25 mL flask and immersed in a preheated oil bath (120° C.). After 6 h, the reaction mixture was cooled to room temperature and ethyl acetate (10 mL) and methanol (0.6 mL) were added to the residue and the mixture was sonicated for 2 min. The resulting precipitate was collected by filtration, washed with cold ethyl acetate (1 mL) and dried on the pump to give crude product. Recrystallization from methanol gave 6-hydroxy-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (1.03 g, 41%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCCNS(=O)(=O)c2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(2-amino-ethyl)-benzenesulfonamide hydrochloride and DBU in DME. ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=2)[C:17](=[O:29])[CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:28][O:27][C:23]1[N:22]=[C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][C:17]2=[O:29])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(N2CCNCC2=O)n1
Reaction time: 1 h
Yield: 115.1 %

Procedure:
35 mL trifluoro acetic acid was added to 5.8 g tert-butyl-4-(6-methoxypyridin-2-yl)-3-oxopiperazine-1-carboxylat in 35 mL dichlormethane under argon. The mixture was stirred for 1 h and evaporated. The residue was purified by chromatographie on silica gel (100% MeOH) to yield 4.5 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:15][C@@H:13]2[OH:14])[CH3:10])[C:4](=[O:32])[CH2:3]1.[Cl:34][C:35]([Cl:39])([Cl:38])[C:36]#[N:37].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:34][C:35]([Cl:39])([Cl:38])[C:36](=[NH:37])[O:14][CH:13]1[O:15][C@H:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]1[NH:11][C:9](=[C:5]1[C:4](=[O:32])[CH2:3][C:2]([CH3:33])([CH3:1])[CH2:7][C:6]1=[O:8])[CH3:10]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC(OC(=N)C(Cl)(Cl)Cl)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranose (100 mg, 0.21 mmol) and trichloroacetonitrile in CH2Cl2 was cooled to 0° C. and 1,8-diazabicyclo(5.4.0)undec-7-en (2 mg) added. The reaction mixture was stirred at 0° C. for 1.5 h and at room temperature for 2 h. The solution was evaporated, and the residue chromatographed using CHCl3/EtOAc 1:1 as the mobile phase to give 2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-3,4,6-tri-O-acetyl-α,β-D-glucopyranosyl trichloroacetimidate (13) (71 mg, 55%).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:15]1([NH:18][C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:2]3[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]4[CH2:12][CH2:11]4)=[O:7])=[CH:4][N:3]=3)[CH:21]=2)=[O:36])[CH2:16][CH2:17]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25.5 mg, 0.10 mmol) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) (30 mg, 0.10 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 90° C. in DMF (1 ml) for 3 hours. The reaction was absorbed onto silica, applied to a bond-elut (5 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to 6-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-N-cyclopropylmethyl-nicotinamide as a cream solid. LCMS: retention time 2.70 min, MH+ 350. NMR: δH [2H6]-DMSO 9.11, (1H, s), 8.84, (1H, t), 8.48, (1H, d), 8.31, (1H, dd), 7.88, (1H, s), 7.81, (1H, d), 7.70, (1H, d), 7.41, (1H, d), 3.20, (1H, t), 2.86, (1H, m), 2.37, (3H, s), 1.06, (1H, m), 0.69, (2H, m), 0.57, (2H, m), 0.46, (2H, m), 0.26, (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[Cu][C:15]#[N:16]>CN(C=O)C.O>[CH2:12]([O:11][C:8]1[C:9]([OH:10])=[C:2]([CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=1)[C:15]#[N:16])[CH3:13]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(C#N)c1O
Yield: 45 %

Procedure:
A mixture of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (200 mg, 0.82 mmol) and copper (I) cyanide in DMF (5 mL) was refluxed overnight. The reaction mixture was diluted with water (20 mL), extracted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. Purified by column chromatography on silica gel to afford Intermediate 51 (70 mg, yield 45%).
Reaction SMILES: [CH2:1]([C:3]([NH2:8])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([F:23])[C:18]=1[O:19][CH2:20][C:21]#[CH:22])[C:13](Cl)=[O:14]>>[CH2:4]([C:3]([NH:8][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([F:23])[C:18]([O:19][CH2:20][C:21]#[CH:22])=[C:10]([F:9])[CH:11]=1)([CH2:6][CH3:7])[C:1]#[CH:2])[CH3:5]
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Reactant: C#CC(N)(CC)CC
Product: C#CCOc1c(F)cc(C(=O)NC(C#C)(CC)CC)cc1F

Procedure:
According to the same method as that of Production Example 1, 1,1-diethyl-2-propynylamine was used in place of 2,2-dimethylpropylamine, 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1,1-diethyl-2-propynyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 52 of the present invention) represented by the formula:
Reaction SMILES: [H-].[Na+].F[C:4]1[C:28]([F:29])=[CH:27][C:26]([I:30])=[CH:25][C:5]=1[C:6]([C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9][NH:10][N:11]([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7]>CN(C)C=O.[Cl-].[Na+].O>[C:15]([O:14][C:12]([N:11]([CH3:19])[N:10]1[C:4]2[C:5](=[CH:25][C:26]([I:30])=[CH:27][C:28]=2[F:29])[C:6](=[O:7])[C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(=CNN(C)C(=O)OC(C)(C)C)C(=O)c1cc(I)cc(F)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)cc(I)cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Sodium hydride (0.256 g, 60% oil dispersion) is added to a solution of tert-butyl 2-(2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-3-oxoprop-1-enyl)-1-methylhydrazinecarboxylate (Preparation 33, 3.20 g) in N,N-dimethylformamide (18 mL) at room temperature, and the mixture is stirred for 2 h. The reaction mixture is poured into a mixture of 100 mL of ice water and 100 mL of saturated brine. The mixture is extracted 3 times with ethyl acetate. The combined organic layers are dried (Na2SO4) and concentrated under a nitrogen stream overnight. The crude product is purified by chromatography, using 200 g of silica gel packed and eluted with acetone/CH2Cl2/heptane (1/3/6), provided 2.76 g (90%) of the title compound as a white foam. Physical characteristics: 1H NMR (CDCl3) δ8.50, 8.31, 7.67, 4.32, 3.37, 1.49, 1.34, 1.25; 13C NMR (CDCl3) δ168.87, 163.97, 160.01, 155.50, 141.76, 131.84, 131.37, 128.46, 127.24, 110.98, 86.73, 78.64, 61.47, 36.09, 28.00, 14.64; MS (ESI+) m/z 491 (M+H)+; TLC (silica gel GF): Rf=0.44 acetone/CH2Cl2/hexane (1/1/3).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[Cl:18].[Br:19]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[C:17]([Br:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[Cl:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCc2ccc(N)c(Cl)c2CC1
Solvent: ClCCl
Product: CCOC(=O)N1CCc2cc(Br)c(N)c(Cl)c2CC1
Reaction time: 0.67 h
Yield: 77.7 %

Procedure:
To a solution of 5.74 g of ethyl 7-amino-6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 100 ml of dichloromethane was added portionwise 3.9 g of N-bromosuccinimide under ice-cooling, followed by stirring for 40 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 5.769 g of ethyl 7-amino-8-bromo-6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:15]=3[CH:16]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[CH:23]=1>C1COCC1>[NH2:1][C:2]1[C:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([NH:21][C:29]([NH:28][C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([CH3:31])[CH:23]=4)=[O:30])=[CH:17][C:15]=3[CH:16]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: COC(=O)c1cnc(N)c(-c2cc3cc(N)ccc3s2)c1
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)Nc4cccc(C)c4)ccc3s2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the solution of methyl 6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate (120 mg, 0.4 mmol. 1 eq) in anhydrous THF (4 mL) at room temperature was added dropwise m-tolylisocyanate (0.051 mL, 1 eq). After the reaction was stirred at room temperature for 4 hours, the solid appeared in the reaction was directly filtered to give methyl 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate as a white solid in amount of 84 mg.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:46]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A 250 mL three necked round bottom flask equipped with a stir bar, thermocouple and nitrogen in/outlet was charged with 5.0 g (12.7 mmol) of bendamustine hydrochloride, 4.2 g (12.9 mmol, 1.01 eq) of docosyl alcohol, 2.7 g (12.9 mmol, 1.01 eq) of dicyclohexyl carbodiimide (DCC), 50 mL of dichloromethane (MDC) and 0.16 g (1.27 mmol, 0.1 eq) of N,N-dimethylamino pyridine (DMAP). The reaction mixture was stirred at room temperature overnight at which time an HPLC analysis indicated the reaction was complete. Solids were removed by vacuum filtration and the wetcake was washed with 50 mL. Two alternate purification procedures were developed. The filtrate was washed with DI water (2×150 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The resultant waxy residue was chromatographed on 80 g of silica gel 60, 230-400 mesh eluting with a gradient beginning with 100% MDC, then 0.5% methanol/MDC and finally 1% methanol/MDC collecting 100-150 mL fractions. Fractions containing the desired product were combined and concentrated to dryness in vacuo. The residue was again triturated with 20 mL of MDC and the undesired solids removed by filtration. The filtrate was concentrated in vacuo to yield 3.65 g (5.5 mmol, 43.1%) of the desired product as a waxy white solid with a purity of 95.7A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.72 Hz, 1H), 7.08 (d, J=2.28 Hz, 1H), 6.78 (dd, J=2.36, 8.72 Hz, 1H), 4.05 (t, J=6.76 Hz, 2H), 3.72 (m, 4H), 3.70 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.44 Hz, 2H), 2.49 (t, J=7.08 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 38H), 0.88 (t, J=6.64 Hz, 3H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=O)[N:16]=1.[CH3:33][CH:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH3:35].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:33][CH:34]([S:36]([NH:39][C:26]([C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[O:23][C:17]1[N:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[N:16]=1)=[O:28])(=[O:38])=[O:37])[CH3:35]
Reactant: CC(C)S(N)(=O)=O
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)NS(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a stirred suspension of 0.33 gram (0.002 mole) of 1,1'-carbonyldiimidazole in 2 mL of tetrahydrofuran was added dropwise a solution of 0.55 gram (0.002 mole) of 2-(4,6-dimethoxypyrimidin-2-yloxy)benzoic acid in 3 mL of tetrahydrofuran. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 30 minutes, and then it was heated to reflux where it was stirred for an additional 30 minutes. After this time the reaction mixture was cooled, and 0.25 gram (0.002 mole) of 1-methylethylsulfonamide (prepared as in Example 1--Step H) was added. Upon completion of addition, the reaction mixture was stirred for 10 minutes, and 0.31 gram (0.002 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for five hours. The reaction mixture was then poured into aqueous dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10% and 20% ethyl acetate in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to yield 0.2 gram of 2-[2-(1-methylethylsulfonylaminocarbonyl)phenoxy]-4,6-dimethoxypyrimidine; m.p. 128°-130° C., Compound 9 in Table I. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.C1(C)C(S(O[CH:35]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]2)(=O)=O)=CC=CC=1>>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Cc1ccccc1S(=O)(=O)OC1CN(C(=O)OC(C)(C)C)C1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1

Procedure:
Analogously to Method I, 9.170 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidinecarboxylate and 11.00 g of tert-butyl 3-(toluenesulphonyloxy)azetidine-1-carboxylate are reacted. The title compound is obtained as a yellow oil. Rf=0.23 (3:1 EtOAc-heptane); Rt=5.01.