Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]([F:19])([F:18])[C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([N:15]2[CH:16]=[CH:17][C:13]([C:12]([F:19])([F:18])[F:11])=[N:14]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl
Temperature: 110 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A mixture of 2-chloro-4-fluorobenzaldehyde (5.0 g, 31.5 mmol), 3-(trifluoromethyl)-pyrazole (4.28 g, 31.5 mmol) and potassium carbonate (6.53 g, 47.3 mmol) in anhydrous N,N-dimethylformamide (40 mL) was stirred for 2 h at 110° C. The reaction mixture was cooled to 0° C., poured into ice water (500 mL) and stirred for 15 min. The precipitate formed was filtered and dried under reduced pressure to afford the title compound (8.1 g), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:34])[C:16](=O)[CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[C:6]([O:35][CH3:36])=[CH:5][CH:4]=1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH3:36][O:35][C:6]1[C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:34])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(OC)c2[nH]c(CCCN(C)C(=O)CC3(O)CC4CCC3C=C4c3ccccc3)nc12
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
To a solution of 310 mg of rac-(1R*,2R*,4R*)-N-[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-2-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-N-methyl-acetamide in 8 mL toluene were added dropwise 0.77 mL of a Red-Al solution (65% in toluene) at 0° C. After stirring for 10 min at 0° C., the cooling bath was removed and stirring was continued for 3 h at rt. The reaction mixture was then carefully poured onto a mixture of 1M NaOH/ice and stirred for 10 min. The aq. phase was extracted with toluene, the combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC using EtOAc-MeOH (2:1) yielded 230 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol as white foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)(O)[O-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cc[nH]n1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
50 mg (0.21 mmol) of the compound from Example 6A and 156 mg (0.64 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole were dissolved in 1 ml of dimethylformamide, 52 mg (0.62 mmol) of sodium bicarbonate were added and the mixture was stirred at RT for 2.5 h. About 10 ml of water were added to the mixture, and the solid formed was purified by preparative HPLC (acetonitrile/water 10:90→95:5, 0.1% TFA added).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:6]3=[N:7][C:2]([C:20]4[S:19][CH:23]=[CH:22][CH:21]=4)=[CH:3][N:4]=[C:5]3[N:10]=[N:9]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(Cn2nnc3ncc(Br)nc32)cc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(Cn2nnc3ncc(-c4cccs4)nc32)cc1
Yield: 18.1 %

Procedure:
A mixture of 6-bromo-1-(4-fluoro-benzyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (100 mg, 0.32 mmol), 2-thiopheneboronic acid (44.8 mg, 0.35 mmol), Pd(PPh3)2Cl2 (11.3 mg, 0.016 mmol), and NaHCO3 (80.6 mg, 0.96 mmol) in DME (2 mL) and water (0.4 mL) was put in a microwave reaction tube and reacted in a microwave reactor at 120° C. for 15 minutes. The reaction mixture was partitioned in ethyl acetate and water, and the organic layer was evaporated. The residue was purified on a silica gel column eluting with EtOAc-Hexane to provide 1-(4-fluoro-benzyl)-6-thiophen-2-yl-1H-[1,2,3]triazolo[4,5-b]pyrazine (18 mg).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH3:10])[CH:8]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[ClH:2].[Cl-:1].[CH2:9]([N:7]1[CH:8]=[C:4]([CH2:3][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[N:6]1)[CH3:10]
Reactant: CCn1cc(CCl)cn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CC#N
Product: CCn1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: [Cl-]
Yield: 95 %

Procedure:
A mixture of 4-chloromethyl-1-ethyl-1H-pyrazole hydrochloride (24.00 g), triphenylphosphine (34.10 g), acetonitrile (250 mL) was heated under reflux for 16 hrs. The reaction mixture was concentrated, and the residue was decanted and washed with diethyl ether (3 times with 200 mL). Toluene was added and the mixture was concentrated under reduced pressure to give [(1-ethyl-1H-pyrazol-4-yl)methyl](triphenyl)phosphonium chloride hydrochloride as amorphous form (57.47 g, yield 95%). NMR (DMSO-d6) δ: 1.22 (3H, t, J=7.2 Hz), 4.01 (2H, q, J=7.2 Hz), 4.66 (1H,brs), 5.01 (2H, d, J=13.8 Hz), 6.93 (1H, s), 7.25 (1H, s), 7.68-7.79 (12H, m), 7.87-7.92 (3H, m).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:22]C1C=C(B(O)O)C=CC=1>>[NH2:22][C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: Nc1cccc(B(O)O)c1
Solvent: O
Product: Nc1cccc(-c2[nH]c3cccc4c3c2CCNC4=O)c1

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (428 mg, 1.61 mmol) and 3-aminobenzeneboronic acid monohydrate (300 mg, 1.94 mmol) were coupled to yield 2-(3-aminophenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 110 mg (25%) as an off-white solid: 1H NMR (300 MHz, d6-DMSO) δ 3.03 (m, 2H), 3.39 (m, 2H), 5.24 (s, 2H), 6.59 (br d, 1H), 6.78 (d, J=7.7 Hz, 1H), 6.84 (m, 2H), 7.18 (m, 2H), 7.52 (d, J=7.9 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 8.04 (br t, 1H), 11.41 (brs, 1H). HRMS (FAB, MH+)Calcd for C17H16N3O: 278.1293. Found: 278.1297. Anal. (C17H15N3O.1.1 H2O) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32]I.[H-].[Na+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]([CH3:32])[CH2:9][CH:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:21][Si:22]([CH:23]([CH3:24])[CH3:25])([CH:26]([CH3:28])[CH3:27])[CH:29]([CH3:31])[CH3:30])=[CH:18][CH:19]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCc1ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Reaction time: 18 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid (E203) in THF under N2 and cooled to 0° C. was added CH3I followed by NaH and the solution was warmed and allowed to stir for 18 h. The mixture was taken up in EtOAc and extracted with NH4Cl(sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-10% MeOH/CH2Cl2 gradient) gave pure 3-(tert-butoxycarbonyl(methyl)amino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid (E204).
Reaction SMILES: COC(=O)[CH2:4][C:5]1[N:9]2[C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]([C:15]3(Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.CNC.[CH3:31][N:32]([CH3:35])[CH:33]=[O:34]>>[CH3:31][N:32]([CH3:35])[C:33](=[O:34])[CH2:4][C:5]1[N:9]2[C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1nnc2n1-c1ccccc1C(C1(Cl)C=CC=CC1Cl)=NC2
Agent: CNC
Product: CN(C)C(=O)Cc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 3, 6-(o-dichlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetic acid methyl ester is reacted with dimethylamine in dimethyl formamide to give N,N-dimethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetamide.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][OH:13])[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:21]Br.O>CN(C=O)C>[F:16][C:17]([F:30])([F:31])[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=1)[CH2:21][O:13][CH2:12][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][CH2:10][CH2:9][O:8]1
Reactant: OCC1(c2ccccc2)OCCO1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)OCCO2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
(2-Phenyl-[1,3]dioxolan-2-yl)methanol (14.82 g, 82 mmol) was dissolved in DMF (200 mL) and cooled with ice and sodium hydride (60% oily) (3.60 g, 90 mmol) was added thereto by dividing into two. The mixture was stirred for 1 hour under cooling with ice and for 2 hours at room temperature and then a solution of 3,5-bis(trifluoromethyl)benzyl bromide (16.5 mL, 90 mmol) in DMF (50 mL) was dropped thereinto during 30 minutes under cooling with ice. After the mixture was stirred for 2 hours under cooling with ice and for 20 hours at room temperature, the reaction mixture was added to water followed by extracting with ethyl acetate. The organic layers were combined, washed with a saturated saline solution and dried over anhydrous sodium sulfate. The residual oily product obtained by evaporation of the solvent in vacuo was purified by a silica gel column chromatography (n-hexane:ethyl acetate=19:1) to give 2-(3,5-bis(trifluoromethyl)benzyloxymethyl)-2-phenyl-[1,3]-dioxolane (34.00 g, 100%) as an oily product. 1H-NMR (DMSO-d6) δ: 3.67 (s, 2H), 3.79-3.84 (m, 2H), 4.02-4.08 (m, 2H), 4.74 (s, 2H), 7.31-7.39 (m, 3H), 7.46-7.49 (m, 2H), 7.89 (s, 2H), 7.96 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24]C3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.ClC[C:36]1[NH:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1>>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:36]3[NH:40][C:39]4[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=4[N:37]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Product: N#Cc1ccccc1Cn1c(N2CCCC(N)C2)cc(=O)n(Cc2nc3ccccc3[nH]2)c1=O

Procedure:
Title compound 20 was prepared by the methods used in the preparation of compound 17, except that 2-chloromethyl benzimidazole was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.67 (d, J=3.0 Hz, 1H), 7.65-7.56 (m, 2 H), 7.47 (d, J=3.3 Hz, 2 H), 7.46 (d, J=3.3 Hz, 1 H), 7.37-7.40 (m, 2 H), 5.52 (s, 3 H), 5.23 (s, 2 H), 3.51 (d, J=9.6 Hz, 1 H), 3.36 (m, 1 H), 2.87-2.92 (m, 2 H), 2.64-2.72 (m, 1 H), 2.09 (m, 1 H), 1.76 (m, 1 H), 1.52-1.64 (m, 2 H). MS (ES) [m+H] calc'd for C25H26N7O2, 456.2; found 456.2.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)SC)#[N:2].[CH2:18]([NH2:22])[CH:19]([CH3:21])[CH3:20]>C(#N)C>[C:1]([N:3]=[C:4]([NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])#[N:2]
Reactant: CSC(=NC1CCCc2ccccc21)NC#N
Reactant: CC(C)CN
Solvent: CC#N
Product: CC(C)CNC(=NC#N)NC1CCCc2ccccc21
Reaction time: 100 h

Procedure:
A solution of 12.3 g of N-cyano-N'-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 20 ml of isobutylamine in 100 ml of acetonitrile was heated at reflux with stirring for 100 hours. The solvent was then removed by evaporation in vacuo. The residual oil was dissolved in methylene chloride and the solution was washed with three 80 ml portions of 3N hydrochloric acid and then dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, and the methylene chloride was removed from the filtrate by evaporation in vacuo, leaving N"-cyano-N-isobutyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as 11.6 g of a pale yellow, viscous oil.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:8]([O:10]CC)=O)[C:3]([O:5]CC)=O.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].CC[O-].[Na+].[Na]>C(O)C>[CH3:13][C:2]1([CH3:1])[C:3](=[O:5])[NH:21][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:8]1=[O:10]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC1(C)C(=O)Nc2ccccc2NC1=O
Yield: 64.7 %

Procedure:
43.0 g of diethyl dimethylmalonate and thereafter 24.7 g of o-phenylenediamine were added to a sodium ethylate solution freshly prepared from 10.5 g of sodium and 400 ml of abs. ethanol under argon. The reaction mixture was heated continuously to 180° C. in the course of 2 hours, whereby ethanol was distilled off continuously. After cooling the dried residue was triturated with dilute hydrochloric acid, the precipitate was filtered off and washed with water and ethanol. After drying in a high vacuum there were obtained 30.2 g of 2,3,4,5-tetrahydro-3,3-dimethyl-2,4-dioxo-1H-1,5-benzodiazepine as a brownish powder, m.p.>270° C. This product was added portionwise under argon to 17.0 g of sodium hydride (about 55%) in 300 ml of abs. dimethylformamide at 0° C. After the exothermic reaction had faded away 27.6 ml of methyl iodide were added and the reaction mixture was warmed to room temperature. Thereafter, it was poured on ice and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried and concentrated up to crystallization. There were obtained 29.5 g of 2,3,4,5-tetrahydro-1,3,3,5-tetramethyl-2,4-dioxo-1H-1,5-benzodiazepine, m.p. 159°-160° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:7][C:8]1[C:9]([CH2:15][CH3:16])=[N:10][NH:11][C:12]=1[CH2:13][CH3:14].[H][H].Cl[CH2:24][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:7][C:8]1[C:12]([CH2:13][CH3:14])=[N:11][N:10]([CH2:24][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:9]=1[CH2:15][CH3:16]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CCc1n[nH]c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)Cn1nc(CC)c(Oc2cc(Cl)cc(Cl)c2)c1CC
Yield: 94.7 %

Procedure:
Sodium hydride (60% dispersion in oil, 250 mg, 6.17 mmol) was added to a stirred solution of 4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole (800 mg, 2.81 mmol, Example 3) in dry N,N-dimethylformamide (5 ml) at 0° C. under nitrogen. The mixture was stirred for 5 minutes during which time hydrogen was evolved and then ethyl 4-chloroacetoacetate (0.42 ml, 3.09 mmol) was added. After 30 minutes the reaction mixture was quenched by the addition of water (0.5 ml) and concentrated under reduced pressure. A solution of the residue in ethyl acetate (50 ml) was washed with saturated aqueous ammonium chloride solution (20 ml) and water (20 ml), dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate:pentane (30:70, by volume) to provide the title compound (1.1 g) as a white solid, m.p. 82–84° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1.S(=O)(=O)(O)[OH:16].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]([NH2:14])=[O:16])[CH2:12][CH2:11][CH2:10]1
Reactant: O=S(=O)(O)O
Reactant: COc1ccccc1C1(C#N)CCC1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1C1(C(N)=O)CCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 1-(2-methoxyphenyl)cyclobutanecarbonitrile (4.29 g) was added sulfuric acid (20 mL, 95-98%)/water (20 mL) and the reaction warmed to 60° C. After 1 h the solution was warmed to 80° C. and heating was continued for 3 h. The reaction was cooled to room temperature and stirred for 16 h. Heating was resumed and after 1 h acetic acid (10 mL) was added. The temperature was increased to 90° C. and heating was continued for 1.75 h. The reaction was cooled to room temperature and then poured onto ˜300 ml of ice and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford the subtitle product (4.19 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:30][C@H:29]([NH2:31])[CH2:28]1)([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C>CC(O)C>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:30][C@H:29]([NH:31][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc(Cl)nc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 70 °C

Procedure:
To a mixture of 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (342 mg, 1.07 mmol), as prepared in Example 2, step 1, and tert-butyl((trans)-3-aminocyclobutyl)carbamate (200 mg, 1.07 mmol) in iPrOH (4 mL) was added DIPEA (0.5 mL). A stir bar was added to the reaction vessel and it was capped and heated in a reaction block at 70° C. for 2 hrs. The solvent was removed and the product was purified via flash chromatography eluting with a gradient of 12%-100% EtOAc in heptanes to afford the title compound (260 mg, 52% yield) as a pink solid.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](Cl)=[O:7])=[N+:2]=[N-:3].[CH2:11]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].O>ClCCCl>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:7])=[N+:2]=[N-:3]
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Reactant: CCCCNCCCC
Solvent: O
Solvent: ClCCCl
Product: CCCCN(CCCC)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutanoyl chloride (10.0 g, 61.8 mmol) in anhydrous DCE (150 mL) was added dibutylamine (21.5 mL, 2 equiv, 0.123 mol) in one portion. A white solid formed immediately and the suspension was stirred vigorously for 3 h at room temperature. DCE (200 mL) and water (200 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with water (2×200 mL) and brine (200 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (15.7 g, quantitative). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 0.91-0.97 (dt, J=7.2, 7.4, 12H), 1.21-1.38 (m, 4H), 1.46 (s, 6H), 1.47-1.57 (m, 4H), 2.47 (s, 4H), 3.25-3.32 (m, 4H). LRMS (ESI+) for C13H26N4O (254.2); Found: 255 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21](NCCN(C)C)=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1.ClC1C=CC(C2N=[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]3C=2CN2CC(OC)=CC2=O)=CC=1.N1CCCCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:39]3)=[CH:20][C:19]2=[O:29])=[CH:6][CH:7]=1
Reactant: COC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Reactant: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Solvent: C1CCNCC1
Product: O=C1C=C(N2CCCCC2)CN1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the experimental for compound 237 from 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one and piperidine. (62 mg, 54%) m/e+=407 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.49 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.62 (d, 1H, D, J=9.2 Hz), 7.47 (d, 2H, D, J=8.4 Hz), 7.25 (t, 1H, D, J=7.3 Hz), 6.85 (t, 1H, D, J=7.3 Hz), 5.09 (s, 2H), 4.69 (s, 1H), 3.56 (s, 2H), 2.99 (m, 4H), 1.63 (m, 2H), 1.53 (m, 4H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of 1-benzhydryl-3-hydroxyazetidine (4.78 g, 20 mmol) in dichloromethane (35 ml) was added triethylamine (2.43 g, 24 mmol) and cooled to 0° C. A solution of methanesulfonyl chloride (1.86 ml, 24 mmol) in dichloromethane (5 ml) was then introduced slowly, and the resulting suspension was stirred at room temperature for 18 h. The volatiles were evaporated, and the residue was extracted with a mixture of ether and ethyl acetate. The combined extract was filtered through Magnosol and the filtrate evaporated to give 6.01 g of a light yellow solid; MS (ES) m/z 318.0 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH2:9][NH2:10].C(N(CC)CC)C>ClCCl>[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH2:9][NH:10][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: CN(C)C(=O)CN
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)CNC(=O)CCl
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A solution of chloroacetyl chloride (1.7 g) in dichloromethane was stirred in an ice-bath, while a solution of N,N-dimethylglycinamide (1.8 g) and triethylamine (2.2 ml) in dichloromethane (20 ml) was added over 20 minutes. The reaction mixture was stirred for 30 minutes and was then washed with water (2×10 ml), and dried over MgSO4. The solution was evaporated under reduced pressure. Thus was obtained N,N-dimethyl chloroacetylglycinamide (2.0 g) as a brown oil, which was used directly, and without further purification.