Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[OH:21][C:22]([CH3:45])([CH3:44])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38](=[O:43])[C:39]([OH:42])([CH3:41])[CH3:40])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:24]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23](=[O:24])[C:22]([OH:21])([CH3:45])[CH3:44])=[CH:30][CH:29]=1)[C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:43])[C:39]([OH:42])([CH3:41])[CH3:40])=[CH:34][CH:33]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)C(=O)c1ccc(Cc2ccc(C(=O)C(C)(C)O)cc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(O)C(=O)c1ccc(C(Br)c2ccc(C(=O)C(C)(C)O)cc2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
11.2 g (0.063 mol) N-bromosuccinimide, and 0.12 g AIBN (2,2-azobis(2-methylpropionitrile)) were suspended in 50 ml carbon tetrachloride and heated to 40° C. under argon. Then a solution of 20.45 g (0.06 mol) of 2-Hydroxy-1{-4-[4-(2-hydroxy-2-methyl-propionyl)-benzyl]-phenyl}2-methyl-propan-1-one (known from PCT Int. Appl. WO 2003040076) in 50 ml carbon tetrachloride was added dropwise over 15 min. After stirring at 75° C. for 3 h, the reaction mixture was cooled to 25° C., filtered, and washed neutral with water, dried over magnesium sulfate and concentrated by evaporation. The raw product (28.4 g) was a brownish resin that was pure enough for further derivatization of the benzylic bromide. The structure was confirmed by 1H-NMR (CDCl3): δ [ppm]: 8.04 (d, 4H), 7.53 (d, 4H), 6.28 (s, 1H, benzylic), 3.95, (s, 2H, OH), 1.61 (s, 12H),
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19](O)=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1N=C[N:24]([C:27](N2C=NC=C2)=[O:28])C=1.C[NH:35]C(N)=O.C(O)(C(F)(F)F)=O>>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:35])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[C:7]([C:27]([NH2:24])=[O:28])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CNC(N)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1=Cn2c(cc3ccc(C(N)=O)cc32)-c2ccccc2C1

Procedure:
(5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N˜10˜-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-N˜6˜-methyl-N˜6˜-[(tetrahydro-2-furanyl)methyl]-) was prepared from (5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6,7-dihydro-3-methoxy-6-[[methyl[(tetrahydro-2-furanyl)methyl]amino]carbonyl]-) using CDI as a coupling reagent in a similar manner as described before; Analytical HPLC method: Solvent A=10% MeO{tilde over (H)}90% H2Õ0.1% TFA, Solvent B=90% MeO{tilde over (H)}10% H2O0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=637.27, HPLC Rt=1.953 min.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH:10]([OH:13])[CH2:9][CH2:8]3)=[CH:3][CH:2]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[C:1]1([CH3:14])[CH:2]=[CH:3][C:4]([C:7]23[CH2:12][CH:11]2[C:10](=[O:13])[CH2:9][CH2:8]3)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C23CCC(O)C2C3)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C23CCC(=O)C2C3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of 5-p-tolyl-bicyclo[3.1.0]hexan-2-ol (1 g, 5.3 mmol) in CH2Cl2 (20 mL) was treated with pyridine (0.6 mL, 7.4 mmol) followed by Dess-Martin periodinane (2.7 g, 6.3 mmol) and warmed to ambient temperature. After 2 h, 3 drops of H2O were added. After 0.5 h, the reaction was quenched with saturated NaHCO3 saturated Na2SO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried and concentrated in vacuo. Purification by silica gel chromatography gave the target compound (760 mg, 77%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42-1.47 (m, 1 H) 1.53-1.61 (m, 1 H) 2.06-2.11 (m, 1 H) 2.20-2.29 (m, 2 H) 2.30-2.36 (m, 1 H) 2.32-2.34 (m, 3 H) 2.37-2.45 (m, 1 H) 7.08-7.18 (m, 4 H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1
Reactant: CNCCN(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 85 °C
Yield: 85 %

Procedure:
N1,N1,N2-trimethylethane-1,2-diamine (138 mg, 1.35 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 428 mg, 1.13 mmol) and DIPEA (0.234 mL, 1.35 mmol) in DMA (3.3 mL), and the mixture was heated at 85° C. for 1.5 h. Part-purification was achieved by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 0-10% CH3OH in CH2Cl2 gave the title compound (444 mg, 85%) as an orange oil; 1H NMR: 2.18 (6H, s), 2.50-2.53 (2H, m), 2.87 (3H, s), 3.26-3.30 (2H, m), 3.95 (3H, s), 6.86 (1H, s), 7.09 (1H, td), 7.30 (1H, d), 7.35-7.40 (1H, m), 8.27 (1H, s), 8.37 (1H, d), 8.47-8.51 (2H, m), 8.79 (1H, s), 8.79-8.82 (1H, m); m/z: ES+ MH+ 463.33.
Reaction SMILES: C[C:2](C)([O:29][SiH2]C(C)(C)C)[C:3]1[CH:28]=[CH:27][C:6]2[C:7](=[O:26])[NH:8][C:9]3[CH:25]=[CH:24][CH:23]=[N:22][C:10]=3[N:11]([C:12](=[O:21])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:5]=2[CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl.C1COCC1>[OH:29][CH2:2][C:3]1[CH:28]=[CH:27][C:6]2[C:7](=[O:26])[NH:8][C:9]3[CH:25]=[CH:24][CH:23]=[N:22][C:10]=3[N:11]([C:12](=[O:21])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:5]=2[CH:4]=1
Reactant: CN1CCN(CC(=O)N2c3cc(C(C)(C)O[SiH2]C(C)(C)C)ccc3C(=O)Nc3cccnc32)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1CCN(CC(=O)N2c3cc(CO)ccc3C(=O)Nc3cccnc32)CC1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Compound l , 15 (15 mg, 0.03 mmol) was dissolved in 1 mL CHCl3, and a solution of 1M tetrabutylammonium fluoride in THF (40 μl) was added. The solution was allowed to stand at room temperature overnight. The solvent was removed in vacuo, and the remaining residue was dissolved in saturated NaHCO washed with ether to remove non-polar impurities, and extracted with CHCl3. The CHCl3 extracts were combined, evaporated, and purified on a short silica gel column to yield 10 mg (86%) of 16 as a waxy solid: 1H NMR (CDCl3) δ 2.05-2.50 (m, 60 H), 2.20 (s, 3 H, CH3), 3.22 (d, J=14 Hz, 1 H), 3.60 (m, 1 H), 4.80 (s, 2 H, CH20), 7.30 (dd, J=7.8, 4.7 Hz, 1 H), 7.44 (d, J=8.1 Hz, 1 H), 7.50 (dd, J=1.6, 7.8 Hz, 1 H), 7.62 (s, 1 H), 7.96 (d, J=8.1 Hz, 1 H), 8.02 (m, 1 H); MS (CI/NH3) m/e 382 (MH+, base), 242, 141, 113.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.Cl[C:14]1[N:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O.O>[CH2:21]([O:20][C:17]1[CH:16]=[N:15][C:14]([N:1]2[CH2:6][CH2:5][CH:4]([C@H:7]3[CH2:9][C@H:8]3[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]2)=[N:19][CH:18]=1)[CH3:22]
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: CCOc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 105 °C

Procedure:
2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (4.0 g, 23.6 mmol) and 2-chloro-5-ethoxypyrimidine (4.12 g, 26.0 mmol) were dissolved in 40 mL of DMA, to which was added cesium carbonate (10.0 g, 30.7 mmol). The reaction was heated at 105° C. overnight. The reaction mixture was cooled to rt and diluted with 40 mL of EtOAc and 40 mL of water. The layers were separated and the aqueous phase extracted with EtOAc (30 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (KP-Sil 340 g SNAP column, Biotage system) eluting with 15-80% EtOAc:hexanes over 11 CV to afford the title compound. LC/MS (m/z): 292 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[Li].BrBr.[CH3:33][S:34]SC>C1(C)C=CC=CC=1.CCOCC>[Cl:19][C:14]1[CH:13]=[C:12]([CH:9]2[O:8][C:5]3=[N:6][CH:7]=[C:2]([S:34][CH3:33])[CH:3]=[C:4]3[CH2:11][CH2:10]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Clc1ccc(C2CCc3cc(Br)cnc3O2)cc1Cl
Reactant: CSSC
Agent: BrBr
Agent: [Li]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CSc1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Temperature: -100 °C
Reaction time: 0.33 h

Procedure:
A solution of 3.6 g of 6-bromo-2-(3,4-dichlorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine in a mixture of 50 ml of toluene and 25 ml of anhydrous ether was cooled to -100° C. under nitrogen and 3.8 ml of 2.9M tert-butyllithium/pentane was added dropwise over about 5 minutes while keeping the temperature below -100° C. This gave a deep blue-green mixture containing the lithio intermediate (i.e., lithium replacing the bromine in the starting material). After 20 minutes, 1.8 ml of dimethyldisulfide was added. The mixture was then allowed to warm to 0° C. and it was partitioned between ether and water. The ether layer was washed with aqueous saturated sodium chloride solution, dried over potassium carbonate and concentrated to a yellow oil which solidified on cooling. Column chromatography on silica gel (20% ethyl acetate/hexane) gave pure product which was further recrystallized from hexane/ethyl acetate to give 2-(3,4-dichlorophenyl)-3,4-dihydro-6-(methylthio)-2H-pyrano[2,3-b]pyridine as colorless needles melting at about 109°-111° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH3:26])(=[O:25])=[O:24])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].CS(C)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH3:26])(=[O:24])=[O:25])(=[O:15])=[O:16])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Reaction time: 0.75 h

Procedure:
A solution of 3-[5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]-phenoxy]propanol (1.16 g, 2.9 mmol), as prepared in the preceding step, anhydrous dimethyl sulfoxide (0.62 mL, 8.7 mmol), and N,N-diisopropylethylamine (1.0 mL, 6.1 mmol) in anhydrous dichloromethane (30 mL) was treated with sulfur trioxide pyridine complex (0.97 g 6.1 mmol) at 0° C. The reaction mixture was stirred for 0.75 h before quenching with 10% aqueous citric acid (40 mL). The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (4×40 mL). The dichloromethane layers were combined and washed with brine, dried, and evaporated to dryness. The material was used without purification in the next step.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[OH2:5].[CH2:6]1[S:10](=[O:12])(=[O:11])[O:9][CH2:8][CH2:7]1>C(O)C>[S:10]([CH2:6][CH2:7][CH2:8][NH:3][CH2:2][CH2:1][NH:4][CH2:8][CH2:7][CH2:6][S:10]([OH:11])(=[O:9])=[O:5])([OH:9])(=[O:12])=[O:11]
Reactant: O=S1(=O)CCCO1
Reactant: NCCN
Reactant: O
Solvent: CCO
Product: O=S(=O)(O)CCCNCCNCCCS(=O)(=O)O
Yield: 88.7 %

Procedure:
Into a four-necked flask containing ethylenediamine (3 g, 0.05 mol) and water (50 g), propanesultone (12.3 g, 0.1 mol) was added dropwise over 30 minutes. The contents were mixed for 2 hours, after which ethanol was added thereto. The mixture was subjected to filtration and then was washed with ethanol to obtain 13.5 g of N,N'-bis(3-sulfopropyl)ethylenediamine (separation yield: 88 wt %).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].C(O)C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.[C:31](=[S:33])=[S:32]>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][S:33][C:31]([N:2]2[C@@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:32])=[CH:25][CH:24]=1
Reactant: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: ClCc1ccc(Cl)cc1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Yield: 57 %

Procedure:
In the same manner as described in Example 16, (3R)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (5.4 g), 2N NaOH (25 ml), 50% ethanol (70 ml), carbon disulfide (1.45 ml) and 4-chlorobenzyl chloride (5.65 g) are reacted and treated. The residue is purified by silica gel column chromatography (solvent, chloroform:methanol:acetic acid=97:2:1) to give the title compound (5.86 g, 57%) as pale yellow powder.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:13]([O:15]CC)=O)[C:8]([O:10]CC)=O.[NH2:22][C:23]([NH2:25])=[O:24]>C(O)C>[CH3:2][O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]1[C:8](=[O:10])[NH:25][C:23](=[O:24])[NH:22][C:13]1=[O:15]
Reactant: CCOC(=O)C(Oc1ccccc1OC)C(=O)OCC
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: COc1ccccc1OC1C(=O)NC(=O)NC1=O
Reaction time: 4 h
Yield: 64.5 %

Procedure:
Sodium (3.2 g; 160 mmol) was dissolved in ethanol (200 ml). Diethyl (2-methoxyphenoxy)malonate (2) (11.2 g; 160 mmol) and urea (2.6 g; 44 mmol) were added to the mixture while being cooled on ice. The mixture was stirred for 4 hours under reflux. After being cooled, ethanol was evaporated, and the residue was dissolved in a small amount of water and made acidic with hydrochloric acid. The mixture was allowed to stand overnight at room temperature. The crystals that precipitated were collected by filtration and dried, to thereby obtain 7.1 g of 5-(2-methoxyphenoxy)-pyrimidine-2,4,6-trione (3). Phosphorus oxychloride (70 ml) and y-collidine (14 ml) were added to this compound and the mixture was stirred for 10 hours under reflux with heat. After phosphorus oxychloride was evaporated, the residue was added to ice-water and the mixture was extracted with ethyl acetate. The reaction mixture was washed with water and dried over anhydrous sodium sulfate, evaporated, and purified by silica gel column chromatography (ethyl acetate: hexane=1:2), to thereby obtain 4.8 g (yield: 39%) of 5-(2-methoxyphenoxy)-2,4,6-trichloropyrimidine (4) as a colorless solid.
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH2:11][CH3:12])=[C:8]([O:13][CH2:14][CH3:15])[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=1[CH:4]=O.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21].C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:24][O:23][C:19]([C:20]1[S:21][C:2]2[C:9]([O:10][CH2:11][CH3:12])=[C:8]([O:13][CH2:14][CH3:15])[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=2[CH:4]=1)=[O:22]
Reactant: CCOc1c([N+](=O)[O-])cc(C=O)c(Br)c1OCC
Reactant: COC(=O)CS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1c([N+](=O)[O-])cc2cc(C(=O)OC)sc2c1OCC
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-3,4-diethoxy-5-nitrobenzaldehyde (1.5 g) in N,N-dimethylformamide (5 ml) were added methyl thioglycolate (1.5 g) and triethylamine (2.2 ml) at 0° C. Stirring was continued at room temperature overnight. 1 M HCl was added and the product was extracted with ether. The organic phase was dried with Na2SO4 and evaporated. The crude product was triturated with methanol.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:41]([CH3:42])[C:40](=[O:43])[N:39]([CH2:44][C@H:45]3[CH2:50][CH2:49][C@H:48]([C:51]([OH:53])=O)[CH2:47][CH2:46]3)[C:38]=2[CH:54]=1.[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][N:65]([C:51]([C@H:48]2[CH2:47][CH2:46][C@H:45]([CH2:44][N:39]3[C:38]4[CH:54]=[C:34]([O:33][CH3:32])[CH:35]=[CH:36][C:37]=4[N:41]([CH3:42])[C:40]3=[O:43])[CH2:50][CH2:49]2)=[O:53])[CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)O)CC1)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethyl amine (0.39 ml, 2.77 mmol) was added to solution of HATU (1.05 g, 2.77 mmol) and trans-4-(6-Methoxy-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexanecarboxylic acid (0.8 g, 2.5 mmol) in DMF (15 ml). The mixture was stirred at room temperature for 20 minutes and then tert-butyl-1-piperazinecarboxylate (0.47 g, 2.52 mmol) was added. The mixture was stirred at room temperature overnight, the solvent was removed under reduced pressure and the crude product was dissolved in DCM (50 ml). The organic solution was washed with HCl 1M (2×40 ml) and then with a saturated solution of NaHCO3. The organic solution was dried over Na2SO4, filtered and the solvent removed. Purification by silica column using cyclohexane/EtOAc (8/1) as eluent gave the titled compound (960 mg, 78%).
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([CH2:10][C:11](O)=O)#[N:9].[C:14](=O)=O.C(=O)(O)[O-].[Na+]>O.O1CCOCC1>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:14][C:10](=[CH2:11])[C:8]#[N:9])[CH2:4][CH2:3]1
Reactant: O=C=O
Reactant: FC1CCNCC1
Reactant: N#CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C#N)CN1CCC(F)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
4-Fluoropiperidine (0.7 g., 0.005 mole) was dissolved in a mixture of 3 ml. of dioxane and 2 ml. of water containing cyanoacetic acid (0.43 g., 0.005 mole). The solution was heated to 65° C. and carbon dioxide evolution began. It was maintained at 60°-65° C. for 21/2 hours and allowed to stand overnight. A solid gummy residue, 1 gm., was obtained upon stripping in a bath at 55° C. and at 1 mm. It was taken up in a small amount of water, made alkaline with sodium bicarbonate and extracted with ether. The organic layer was water washed and dried over anhydrous sodium sulfate. After solvent stripping, the product was obtained as a colorless oil, 0.7 g., of analytical purity.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[CH:34]=[O:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:34]=[O:35])=[CH:4][CH:5]=1
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc3ccccc3c2C=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (11.13 g), 2-hydroxy-1-naphthaldehyde (5.96 g), anhydrous potassium carbonate (5.03 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, and dried with air to give crystals (13.83 g, 89%) of 2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthaldehyde. Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 141-142° C.
Reaction SMILES: FC(S(O[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([NH:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:10]=1)(=O)=O)(F)F.O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C>[C:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][NH:23][C:11]1[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCNc1nc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C#N)cc2)n1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1nc(-c2ccc(C#N)cc2)cc(N2CCOCC2)n1
Temperature: 90 °C

Procedure:
2-({2-[(tert-butoxy)carbonylamino]ethyl}amino)-6-(4-cyanophenyl)pyrimidin-4-yl (trifluoromethyl)sulfonate (134 mg, 0.275 mmol) was dissolved in a 2M solution of morpholine in acetonitrile and the resulting solution heated to 90° C. for 18 h. The solution was cooled, water added and the suspension extracted thoroughly with ethyl acetate. Concentration of the combined organic layers gave a crude solid which was chromatographed (silica gel, 2% methanol/methylene chloride) to afford 234 mg of (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-6-morpholin-4-ylpyrimidin-2-yl]amino}ethyl)carboxamide as a off white solid. Removal of the tert-butoxy protecting group was accomplished in the following manner: the (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-6-morpholin-4-ylpyrimidin-2-yl]amino}ethyl)carboxamide produced as described above was dissolved in anhydrous hydrogen chloride in dioxane (2 mL of a 2M solution) and stirred at room temperature for 2 h. Concentration gave 134 mg of 4-{2-[(2-aminoethyl)amino]-6-imidazolyl-4-ylpyrimidin-4-yl}benzenecarbonitrile as its (2×) hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[S:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)cs1
Product: O=C(Cl)c1cc(Br)cs1

Procedure:
According to the procedure of Example 32, 2.48 g (12.0 mmoles) of 4-bromo-2-thiophenecarboxylic acid (prepared according to Lawesson, S. O., Arkiv. for Kemi. 11:317 (1957)) and 10 ml of thionyl chloride were combined and heated. The reaction gave 2.99 g of 4-bromo-2-thiophenecarbonyl chloride as a dark oil. Following the procedure of Example 32, the acid chloride, 2.11 g (10.0 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 3.67 g (30.0 mmoles) of 4-(N,N-dimethylamino)pyridine were reacted in N,N-dimethyl-formamide to give 4.03 g of a crude orange solid. Recrystallization gave 2.67 g (6.68 mmoles, 66.8% yield) of title compound as a yellow crystalline solid, m.p. 217-219° C. (dec.) (2-butanone).