Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[F:26]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:19][C:18]=1[F:26]
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: CCC(=O)NC1CCc2c(-c3ccc(Cl)c(F)c3)cncc21
Yield: 87 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-4) was reacted with 4-chloro-3-fluorophenylboronic acid to give the title compound as grey solid in 87% yield. MS: 319.1 (M+H+, 1Cl).
Reaction SMILES: [OH:1][CH:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:19]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[CH3:7][C:6]1([CH3:8])[CH2:5][CH2:4][N:3]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH:2]1[O:1][CH3:19]
Reactant: CC1(C)CCN(C(=O)OCc2ccccc2)C1O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC1N(C(=O)OCc2ccccc2)CCC1(C)C
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 895.4 %

Procedure:
In a 500 ml flask was dissolved phenylmethyl 2-hydroxy-3,3-dimethyl-1-pyrrolidinecarboxylate (0.0475 mol, 11.8 g) in 100 ml methanol. Catalytic Pyridinium p-toluenesulfonate (0.00475 mol, 1.19 g) was added and the reaction was stirred at 20° C. for 45 min. The reaction was quenched with triethylamine (3 ml) and concentrated. The resulting crude oil was purified on 120 g silica (chloroform/ethyl acetate) yielding 11.2 g (90%) of phenylmethyl 3,3-dimethyl-2-(methyloxy)-1-pyrrolidinecarboxylate as a clear oil. LCMS (ESI+)=286 m/z (MNa+). 1H NMR (400 MHz, CDCl3)— rotomers δ 7.39-7.32 (m, 5H), 5.24-5.13 (m, 2H), 4.68 and 4.57 (s, 1H), 3.52-3.46 (m, 4H), 3.31 (s, 2H), 1.97-1.90 (m, 1H), 1.58-1.54 (m, 1H), 1.10 (s, 3H), 0.9 (s, 3H).
Reaction SMILES: [OH-].[Na+].[C:3](OC([O-])=O)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O1CCCC1.[CH2:19]([NH:22][CH2:23][C@H:24]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH3:25])[CH:20]=[CH2:21]>O>[CH2:19]([N:22]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:23][C@H:24]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH3:25])[CH:20]=[CH2:21]
Reactant: C=CCNC[C@@H](C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCN(C[C@@H](C)NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A 2N aqueous NaOH solution (50 mL) and 6.1 g of tert-butyl dicarbonate were added to a tetrahydrofuran (100 mL) solution of 7 g of the compound obtained in Step 1, stirring at room temperature and reacted at room temperature for 6 hours. After the completion of reaction, 100 mL of water was added, followed by two extractions with 100 mL of ethyl acetate. The combined organic layer was washed with 100 mL of saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 8 g of the compound of interest as a yellow oil (86%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([S:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([S:9]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH:6]=[CH:5][C:4]=1[NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:23])([F:24])[F:22]
Reactant: COc1cc(S(=O)(=O)c2ccncc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccncc2)cc1O)C(F)(F)F
Yield: 12 %

Procedure:
To a stirred suspension of N-[2-methoxy-4-(4-pyridylsulfonyl)phenyl]-3,3,3,-trifluoro-2-hydroxy-2-methyl propanamide (1.30 g) and sieve dried methylene chloride (50 mL) was added boron tribromide (1.6 mL of a 1.0 M solution in methylene chloride), and the mixture (a gummy ball of material and solvent) was stirred at reflux for 2 hours and then stirred overnight at room temperature. The reaction mixture was poured into water, made basic with saturated sodium bicarbonate solution and extracted with methylene chloride (2×250 mL; discarded) followed by ethyl acetate (100 mL). The ethyl acetate solution was dried, filtered, evaporated to a brown oil and purified by chromatography twice (eluent ethyl acetate and eluent methylene chloride-ethyl acetate (1:4)) to yield the title compound (0.15 g); mp 218-220° C. Analysis for C15H13F3N2O5S: Calculated: C, 46.16; H, 3.36; N, 7.18: Found: C, 45.87; H, 3.47; N, 6.91. ##STR2##
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:14])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]=2[C:6](=[O:13])[CH2:5]1.O>C(O)C>[OH:13][CH:6]1[CH2:5][C:4]([CH3:14])([CH3:3])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]1=2
Reactant: CC1(C)CC(=O)c2sccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(O)c2sccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (0.97 g, 25.5 mmol) was added to a solution of 5,6-dihydro-5,5-dimethyl-7H-thieno [3,2-b]pyran-7-one (3.1 g, 17.0 mmol) in ethanol (50 mL) and stirred at rt for 2 h. An additional 0.97 g of sodium borohydride was added and the mixture was stirred 16 h. The mixture was poured into water and extracted with dichloromethane. The dichloromethane solution was washed with water (5×) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product, 2.96 g (95%), as a brown oil: IR (neat): 3373, 2976, 1561 and 1400 cm-1 ; MS: m/z 185 (MH+ ; 1H NMR (CDCl3): δ1.34(s, 3H), 1.45(s, 3H), 1.87(m, 1H), 1.94(d, J=7.0 Hz, 1H, exchanges with D2O), 2.16(m, 1H), 4.88(m, 1H), 6.57(d, J=5.4 Hz, 1H), 7.13(d, J=5.4 Hz, 1H). This oil was used without further purification in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=[O:16].N1C[CH2:22][O:21][CH2:20]C1>>[N:2]1([CH2:3][CH2:4][CH2:5][C:6]2[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[NH:8][C:7]=2[CH:15]=[O:16])[CH2:1][CH2:22][O:21][CH2:20][CH2:17]1
Reactant: C1COCCN1
Reactant: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Product: O=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2

Procedure:
3-(3-Morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde was prepared utilizing the procedure described for 3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (Example 1) but substituting dimethylamine with morpholine.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[N+:19](CCC(C1C=CC=CC=1)=O)([O-:21])=[O:20].[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CC[N+](=O)[O-])c1ccccc1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc([N+](=O)[O-])c1
Yield: 98 %

Procedure:
Compound 9g was synthesized by a procedure similar to that described for 9a using commercially available 3-nitropropiophenone (8g, 5.0 g, 0.028 mol), TBDMSOTf (7.1 mL, 30.7 mmol), and Et3N (6.2 mL) in CH2Cl2 (50 mL). After purification on alumina, 8.0 g (98%) of 9g was isolated as colorless oil: 1H NMR (CDCl3) δ 8.34-8.30 (m, 1H), 8.12-8.06 (m, 1H), 7.80-7.75 (m, 1H), 7.52-7.42 (m, 1H), 5.40 (q, 1H, J=6.9 Hz), 1.78 (d, 3H, J=6.9 Hz), 1.02 (s, 9H), −0.02 (s, 6H); 13C NMR (CDCl3) δ 148.8, 141.6, 131.3, 129.0, 122.1, 120.5, 108.6, 106.8, 25.9, 18.4, 12.0, −3.8. C15H23NO3Si.
Reaction SMILES: [N:1](C(C1C(C2C=CC=CC=2C(C2C=CC(Cl)=CC=2)=O)=C(C)ON=1)C)=[N+:2]=[N-:3].CN(C=O)C.C(#N)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([C:44]2[C:45]([F:58])=[N:46][CH:47]=[CH:48][C:49]=2[C:50]2[C:51]([CH3:57])=[N:52][O:53][C:54]=2[CH2:55]O)=[O:43])=[CH:38][CH:37]=1>O>[N:1]([CH2:55][C:54]1[O:53][N:52]=[C:51]([CH3:57])[C:50]=1[C:49]1[CH:48]=[CH:47][N:46]=[C:45]([F:58])[C:44]=1[C:42]([C:39]1[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][CH:40]=1)=[O:43])=[N+:2]=[N-:3]
Reactant: Cc1onc(C(C)N=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: Cc1noc(CO)c1-c1ccnc(F)c1C(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1noc(CN=[N+]=[N-])c1-c1ccnc(F)c1C(=O)c1ccc(Cl)cc1

Procedure:
A procedure similar to the synthesis of (2-(3-(1-azidoethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone in Example 16 was followed, except that DMF was substituted by a mixture of acetonitrile and water; and that (4-Chlorophenyl)(2-fluoro-4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)pyridin-3-yl)methanone was used as starting material. LC/MS m/z 372 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:14][CH:15]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Oc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc(O)cc2)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
3-Cyanophenylboronic acid (1.18 g, 8.03 mmol), 4-bromophenol (1.16 g, 6.69 mmol) and sodium carbonate (2.12 g, 20.07 mmol) were dissolved in dioxane (20 mL) and water (8 mL) and the reaction mixture was degassed under nitrogen. Tetrakistriphenylphosphinepalladium (0) (0.77 g, 0.67 mmol) was added and the reaction was stirred at 110° C. for 2 hours. The mixture was cooled to room temperature, filtered through pad of Arbocel™ and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was dried over anhydrous magnesium sulphate, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in heptane to give the title compound as a pale yellow solid (0.58 g, 44%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([C@@:32]1([CH2:47]CO)[CH:36]([CH3:37])[C:35](=[O:38])[N:34]([C@@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([C@@:32]1([CH2:47][CH2:1][Br:5])[CH:36]([CH3:37])[C:35](=[O:38])[N:34]([C@@H:39]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40])[CH2:33]1)=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CCO)C(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CCBr)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
Carbon tetrabromide (1.64 g, 4.95 mmol) and triphenylphosphine (1.30 g, 4.95 mmol) were sequentially added to a solution of (3S)-3-(2-hydroxyethyl)-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (1.56 g, 4.50 mmol) in dichloromethane (20 mL) in a nitrogen atmosphere at 0° C. After heating to room temperature, the reaction solution was stirred for 10 minutes and concentrated to about 5 mL. The residue was purified by silica gel column chromatography (dichloromethane→hexane:ethyl acetate=4:1→2:1→1.5:1) to give 1.30 g (70%) of the diastereomer mixture title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][OH:20])[C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][O:20][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])[C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCCCCCCCC(=O)N(CCO)CCO
Product: CCCCCCCCCCCC(=O)N(CCOC(=O)C(C)(C)C)CCOC(=O)C(C)(C)C

Procedure:
N,N-bis(2-trimethylacetoxyethyl)lauramide was prepared by the procedure of example 1 from 29 gms. (0.1 mole) of N,N-bis(2-hydroxyethyl)lauramide and 24 gms. (0.2 mole) of trimethylacetyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [CH:1]([O:5][C:6](=[O:16])[CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])([CH2:3][CH3:4])[CH3:2].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH:1]([O:5][C:6](=[O:16])[CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)OC(=O)CC(C)CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCC(C)OC(=O)CC(C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
A mixture of the oily ester, thus obtained, one ml of pyridine and 485 mg of p-toluenesulphonyl chloride was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water, extracted with ethyl acetate, the extract washed with dilute sulphuric acid, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and ethyl acetate (20:1) as eluent to give 647 mg of the subtitle compound having the following physical characteristics:
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:27]=[C:26]([S:28][CH3:29])[CH:25]=[CH:24][C:4]=2[S:5][C:6]=1[C:7]([NH:9][CH:10]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].[OH:30]O>C(O)(=O)C>[OH:1][C:2]1[C:3]2[CH:27]=[C:26]([S:28]([CH3:29])=[O:30])[CH:25]=[CH:24][C:4]=2[S:5][C:6]=1[C:7]([NH:9][CH:10]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:8]
Reactant: OO
Reactant: CSc1ccc2sc(C(=O)NC=C(c3ccccc3)c3ccccc3)c(O)c2c1
Solvent: CC(=O)O
Product: CS(=O)c1ccc2sc(C(=O)NC=C(c3ccccc3)c3ccccc3)c(O)c2c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A mixture of 3-hydroxy-5-methylthio-N-(2,2-diphenylethenyl)-benzo[b]thiophene-2-carboxamide (0.42 g, 0.0010 moles) and 30% H2O2 (0.80 ml) in acetic acid (10 ml) was stirred at 75° for 30 minutes. The reaction was cooled to 0° and the yellow precipitate was filtered, acetic acid washed and dried under vacuum, to afford 0.38 g (88%) of 3-hydroxy-N-(2,2-diphenyl)ethenyl-5-methylsulfinylbenzo[b]thiophene-2-carboxamide. MS gave Mol ion at 433.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>>[CH2:11]([N:13]([CH2:14][CH3:15])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:12]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCNCC
Product: CCN(CC)C(=O)c1ccccc1Cl

Procedure:
2-Chlorobenzoyl chloride is reacted with diethylamine using General Method E1 or E2 to produce the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH:19]1([NH:22][CH:15]2[CH2:16][CH2:17][N:12]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:11]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: O=C1CCN(c2nc(-c3ccccc3)no2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one (400 mg), cyclopropylamine (120 μL), sodium triacetoxyborohydride (420 mg), and glacial acetic acid (0.20 mL) in dichloromethane (7 mL) is stirred for two days at room temperature. Dichloromethane is added and the mixture is washed with aqueous K2CO3 solution. The organic phase is dried over Na2SO4 and concentrated in vacuo to afford the title compound. TLC: rf=0.30 (silica gel, CH2Cl2/MeOH 95:5); Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:6])[CH3:2].Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[CH:23][C:22]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[CH:29]1([CH2:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([N:16]3[CH2:17][CH2:18][CH:13]([C:10]4[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:19])=[CH:8][CH:9]=4)[CH2:14][CH2:15]3)=[C:22]([O:32][CH3:33])[CH:23]=2)[CH2:30][CH2:31]1
Reactant: CCNC(=O)C(C)c1ccc(C2CCNCC2)cc1
Reactant: COc1cc(OCC2CC2)ccc1Br
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCNC(=O)C(C)c1ccc(C2CCN(c3ccc(OCC4CC4)cc3OC)CC2)cc1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
100 mg (0.38 mmol) N-Ethyl-2-(4-piperidin-4-yl-phenyl)-propionamide (VI.1) in 2 mL DMSO are added to a mixture of 99 mg (0.38 mmol) 1-bromo-4-cyclopropylmethoxy-2-methoxy-benzene, 106 mg (0.77 mmol) potassium carbonate, 7.3 mg (0.038 mmol) copper(I) iodide and 8.8 mg (0.077 mmol) (L)-proline under inert gas atmosphere. The mixture is stirred for 7 d at 90° C. and for additional 4 d at 100° C. After that time, the mixture is filtered and the solvent is evaporated. The residue is purified by HPLC (column: Waters XBridge 50; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[CH2:23]([CH:30]1[CH2:33][C:32](=O)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([C@H:30]1[CH2:31][C@H:32]([N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH2:33]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Reactant: O=C1CC(Cc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN([C@H]2C[C@H](Cc3ccccc3)C2)C1

Procedure:
The title compound, MS: m/e=372.3 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and 3-benzyl-cyclobutanone.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:49]=[CH:48][C:39]([C:40]([NH:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])=[O:41])=[CH:38][C:37]=1[O:50][CH3:51]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:49]=[CH:48][C:39]([C:40]([NH:42][CH2:43][CH2:44][N:45]([CH3:46])[CH3:47])=[O:41])=[CH:38][C:37]=4[O:50][CH3:51])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1N
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 72 %

Procedure:
A mixture of 0.0642 g (0.194 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0542 g (0.29 mmole) of toluenesulfonic acid monohydrate, 0.0451 g (0.194 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 16 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) to give 0.0743 g of 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)-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide (I-253) as a white solid.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[CH:18][N:17]([CH3:20])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[C:21]([N:6]1[C:5]2[CH:25]=[CH:26][C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]=[CH:18][N:17]([CH3:20])[N:16]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: Cn1cnc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 110 °C
Yield: 81.5 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(1-methyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (32 mg, 0.078 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (21 mg, 0.095 mmol), tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) and 2M aq. Na2CO3 (0.2 ml, 0.4 mmol). The reaction mixture is heated under Argon at 110° C. for 2 hours. The residue is diluted with EtOAc, washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-3% 7M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (27 mg, 82%) as an off-white solid. LCMS (ESMS): m/z 425.66 (M++1)