Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([C:12]12[CH2:19][CH2:18][N:15]([CH2:16][CH2:17]1)[C:14](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]2=[O:27])[CH:10]=[CH2:11].C[Si](Cl)(C)C.CN(P(N(C)C)(N(C)C)=O)C>[Cu].C1(C)C=CC=CC=1>[CH2:9]([C:12]12[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]1)[CH:14]([CH:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]2=[O:27])[CH:10]=[CH2:11]
Reactant: Br[Mg]c1ccccc1
Reactant: C=CCC12CCN(CC1)C(=Cc1ccccc1)C2=O
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: C=CCC12CCN(CC1)C(C(c1ccccc1)c1ccccc1)C2=O
Temperature: 0 °C
Yield: 67.5 %

Procedure:
Copper(I) bromide dimethyl sulfide complex (1.06 g, 5.16 mmol) and 100 ml of toluene were placed in a reaction vessel, which was immersed into an dry-ice acetone bath. Phenylmagnesium bromide (3.0M in ether, 42 ml, 126 mmol) was slowly added to the copper catalyst keeping the inner temperature below -60° C. To this yellow-white suspension was added a solution prepared from 4-allyl-2-benzylidene-1-azabicyclo[2.2.2]octane-3-one (25.9 g, 103 mmol), trimethylsilyl chloride (31.4 ml, 247 mmol), HMPA (43 ml, 247 mmol) and toluene (120 ml) keeping below -60° C. After addition was completed, the reaction mixture was warmed up to 0° C. The reaction was quenched with 14.5 ml of acetic acid at -60° C. Water was added to the reaction mixture, which was neutralized with Na2CO3 (pH=6.5). The resulting solution was worked-up by an ordinal procedure (extraction with ether at pH=6.5, and then at pH=8.0, washing with brine, drying over Na2SO4, concentration by evaporation) to provide a crude product, which was triturated with ether to afford 4-allyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-one, 58 (23.04 g, 68%).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:7][CH:6]([NH2:8])[C:5]1([CH3:10])[CH3:9])[CH3:2].Cl[C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)(C)(C)C.ClCCCl>[CH2:1]([O:3][CH:4]1[CH2:7][CH:6]([NH:8][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=2)[C:5]1([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC1CC(N)C1(C)C
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: CCOC1CC(Nc2nc(SC)ncc2C#N)C1(C)C
Temperature: 70 °C
Yield: 100 %

Procedure:
A solution of 3-ethoxy-2,2-dimethylcyclobutanamine (1.0 equiv.) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.1 equiv.) in tert-butanol/1,2-dichloroethane (0.5 M) was treated with potassium carbonate powder (3.0 equiv.). The resulting reaction mixture was then heated at 70° C. under nitrogen for 3 h. After cooling, ethyl acetate was added and the mixture was vigorously stirred. The solid was removed by vacuum-filtration. The filtrate was concentrated and further dried to give (100% yield) of waxy, yellow solid, which was used in the next step without further purification. MS (ESI) m/z 293.0 [M+1]+.
Reaction SMILES: I[C:2]1[C:3]([CH3:12])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([Li])CCC.[OH2:18].[O:19]1[CH2:23]CCC1>CCCCCC.C(=O)=O>[CH3:11][N:5]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:2]([C:23]([OH:19])=[O:18])[C:3]([CH3:12])=[N:4]1
Reactant: O
Reactant: Cc1nn(C)c(C(F)(F)F)c1I
Reactant: C1CCOC1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1nn(C)c(C(F)(F)F)c1C(=O)O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
4-Iodo-1,3-dimethyl-5-trifluoromethylpyrazole (8.7 g, 30 mmol) was dissolved in tetrahydrofuran (87 ml), and a solution (1.6 M, 28 ml) of n-butyl lithium in hexane was slowly added under an argon atmosphere with cooling with dryice-acetone (not higher than −60° C.). After stirring at −70° C. for 30 min, the mixture was gradually warmed to room temperature while blowing in carbon dioxide. The reaction mixture was poured into water, the organic layer was removed, and the aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained crude crystals were washed with hexane to give the desired compound (4.67 g) as crystals.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[N:8][C:4]=2[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:16]=[CH:15][C:5]4[NH:6][C:7]([CH2:9][N:10]5[CH2:14][CH2:13][CH2:12][CH2:11]5)=[N:8][C:4]=4[CH:3]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc2[nH]c(CN3CCCC3)nc2c1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4[nH]c(CN5CCCC5)nc4c3)nc2)cc1

Procedure:
Prepared according to general working method I from 5-iodo-2-pyrrolidin-1-ylmethyl-1H-benzimidazole (200 mg, 0.61 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (131 mg, 0.61 mmol).
Reaction SMILES: [OH2:1].[OH-].[Na+].[OH:4][C:5]1[CH2:9][CH2:8][C:7](=O)[C:6]=1[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(O)(=O)C>[OH:1][CH:8]1[CH2:9][C:5](=[O:4])[C:6]([CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7]1
Reactant: O
Reactant: COC(=O)CC/C=C\CCC1=C(O)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)CC/C=C\CCC1=CC(O)CC1=O
Temperature: 100 °C
Reaction time: 26 h
Yield: 71 %

Procedure:
To the compound [VIII-2] (2.50 g) obtained above are added water (123.8 g) and acetic acid (0.19 g), and the pH value of the mixture is adjusted to pH 4.2 with 5% aqueous sodium hydroxide solution and the mixture is heated with stirring at 100° C. for 26 hours. After completion of the reaction, the reaction mixture is cooled and extracted twice with methyl isobutyl ketone (50 ml). The organic layer is separated and concentrated to give a mixture (1.78 g, yield; 71%) of 4-hydroxy-2-(6-methoxycarbonyl-cis-3-hexenyl)-2-cyclopentenone (racemic 4-hydroxycyclopentenone) and 3-hydroxy-2-(6-methoxycarbonyl-cis-3-hexenyl)-2-cyclopentenone [IX-2] (ratio thereof=4.9:5.1).
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH3:13])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]\[C:9]([OH:11])=O.[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].C(Cl)(=O)OCC.C(NCC)C>ClCCl>[CH2:14]([N:16]([CH2:17][CH3:18])[C:9](=[O:11])/[CH:8]=[C:7](/[CH3:12])\[CH2:6][CH2:5]/[CH:4]=[C:3](\[CH3:13])/[CH2:2][OH:1])[CH3:15]
Reactant: C/C(=C/C(=O)O)CC/C=C(\C)CO
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)/C=C(/C)CC/C=C(\C)CO

Procedure:
Following the same manner as in Example 5, the reaction and after-treatment were conducted by using 1.0 g of (E,E) and (Z,E)-8-hydroxy-3,7-dimethyl-2,6-octadienoic acid, 0.9 ml of triethylamine, 0.62 ml of ethyl chlorocarbonate and 0.67 ml of diethylamine in 20 ml of dichloromethane to afford 850 mg of the end product.
Reaction SMILES: N1([O:10][C:11](=[O:43])[C:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[CH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)C2C=CC=CC=2N=N1.[CH3:44][O-].[Na+]>CO.Cl>[CH3:44][O:10][C:11](=[O:43])[C:12]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH:36]3[S:40][C:39](=[O:41])[NH:38][C:37]3=[O:42])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[CH:13][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: C[O-]
Reactant: Cc1cc(C)cc(C=C(C(=O)On2nnc3ccccc32)c2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1cc(C)cc(C)c1)c1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Yield: 62 %

Procedure:
To a solution of 48 (240 mg, 0.4 mmol) in methanol (10 mL) was added sodium methoxide (0.5 N in methanol, 2 mL). After 10 min the mixture was diluted with 1N HCl (2 mL) and the product was extracted into ethyl acetate (50 mL), washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography using hexanes:ethyl acetate (3:2) to yield 49(122 mg, 62%) as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (br s, 1H), 7.71 (s, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.92 (s, 1H), 6.68 (s, 2H), 4.91 (dd, J=8.8 and 4.4 Hz, 1H), 3.73 (s, 3H), 3.37 (dd, J=14.0 and 4.4 Hz, 1H), 3.12 (dd, J=14.0 and 8.8 Hz, 1H), 2.12 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].CCOC(C)=O.CCCCCC>C(N(CC)CC)C.[Cu]I.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>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:15])[CH3:14]
Reactant: Clc1ccc2ccccc2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: C[Si](C)(C)C#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Chloroquinoline (1.02 g, 6.17 mmol), CuI (12.1 mg, 0.622 mmol), and PdCl2(PPh3)2 (22.7 mg, 0.0317 mmol) were dissolved in triethylamine (20.6 mL), followed by stirring for 5 min. To the resulting mixture, trimethylsilyl acetylene (1.34 mL, 9.44 mmol) was added dropwise at 60° C., followed by heating. The completion of the reaction was confirmed by TLC (EtOAc/Hexane=1:10). When the reaction was completed, the reactant was cooled down to room temperature and extracted with a saturated aqueous solution of NaCl and ethyl acetate, to thereby separate an organic layer. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/Hexane=1:10, R.f: 0.4), to thereby obtain 2-((trimethylsilyl)ethynyl)quinoline (1.289 g, 93%) as brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:13]=[C:14]([CH3:16])[CH3:15].S(=O)(=O)(O)O>ClCCl>[C:14]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:16])([CH3:15])[CH3:13]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(OC(C)(C)C)c1
Reaction time: 48 h

Procedure:
To a solution of ethyl 3-hydroxybenzoate (20 g, 0.13 mol) in dichloromethane (200 ml) were added isobutene (about 30 g) and conc. sulfuric acid (0.5 ml), and the mixture was left for 2 days. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give the objective substance (17.3 g, 63%) as an oil.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[O:10])[NH:8][CH:9]=1.I[CH2:13][CH2:14][CH2:15][O:16][CH3:17]>C(O)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]([O:11][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[C:7](=[O:10])[NH:8][CH:9]=1
Reactant: COCCCI
Reactant: O=c1[nH]cc(Br)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCCCOc1cc(Br)c[nH]c1=O
Reaction time: 0.25 h

Procedure:
To a 1.4M NaOH solution at 0° C. are added 0.9 mol 5-bromo-3-hydroxy-1H-pyridin-2-one [34206-49-0]. The mixture is allowed to stir for 15 minutes and 0.9 mmol 1-iodo-3-methoxypropane [61542-10-7] are added carefully at 0° C. The mixture is stirred at room temperature for 3 hours, then neutralized with acetic acid to pH 7. The mixture is extracted with chloroform (10×) and the organic layer is dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60 F) and identified based on its Rf value.
Reaction SMILES: [F:1][C@@:2]1([CH2:15]OS(C(F)(F)F)(=O)=O)[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[N-:24]=[N+:25]=[N-:26].[Na+].CC(OC)(C)C.O>CN(C=O)C>[N:24]([CH2:15][C@:2]1([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)=[N+:25]=[N-:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(COS(=O)(=O)C(F)(F)F)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,1-Dimethylethyl (3S)-3-fluoro-3-({[(trifluoromethyl)sulfonyl]oxy}methyl)-1-piperidinecarboxylate (1 wt) is dissolved in N,N,-dimethylformamide (3 vol) at 20° C. and sodium azide (1.1 eq, 0.20 wt) is added. The resulting suspension is stirred at 20-30° C. for 6 h. TBME (5 vol) and water (9 vol) are added. The mixture is stirred for 5 min and the layers are separated. The aqueous phase is extracted with TBME (5 vol) and the TBME phases are combined. The combined organics are washed with water (2×5 vol), filtered and concentrated under reduced pressure to give the title compound as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19](I)=[CH:20][C:12]1=2)(=[O:10])=[O:9].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][NH:14][C:13]2[N:17]=[CH:18][C:19]([C:32]3[CH:31]=[N:30][C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:34][CH:33]=3)=[CH:20][C:12]1=2)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1ccccc1Cl)N1CCNc2ncc(I)cc21
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(S(=O)(=O)c3ccccc3Cl)CCN4)cn2)CC1
Yield: 41 %

Procedure:
1-(2-Chlorobenzenesulfonyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (44 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a yellow solid (41% yield). M.p. 164-165° C., LCMS: m/z=486.79 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (s, 3H), 2.54 (t, J=5.1 Hz, 4H), 3.39-3.42 (m, 2H), 3.60 (t, J=4.5 Hz, 4H), 3.88 (t, J=4.5 Hz, 2H), 5.17 (bs, 1H), 6.69 (d, J=8.8 Hz, 1H), 7.39-7.45 (m, 1H), 7.51-7.56 (m, 3H), 7.73 (s, 1H), 8.01 (d, J=1.0 Hz, 1H), 8.13 (dd, J=8.6 Hz, 1.0 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H).
Reaction SMILES: O=[CH:2][CH:3]=[CH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:7][CH:6]=1.[CH:28]1([O:33][C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=2[O:41][CH3:42])[NH2:37])[CH2:32][CH2:31][CH2:30][CH2:29]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH:28]1([O:33][C:34]2[CH:35]=[C:36]([NH:37][CH2:2][CH:3]=[CH:4][C:5]3[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:10])=[CH:26][CH:27]=3)[CH:38]=[CH:39][C:40]=2[O:41][CH3:42])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CC=O)cc1
Reactant: COc1ccc(N)cc1OC1CCCC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(NCC=Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1OC1CCCC1
Reaction time: 0.17 h

Procedure:
To a stirred solution at room temperature of compound XVI (210 mg, 0.57 mmol), 3-cyclopentyloxy-4-methoxy-aniline (125 mg, 0.60 mmol) or ArNH2 (1.05–1.2 equiv.) in anhydrous THF (7 ml) under nitrogen were added dibutyltin dichloride (3.5 mg, 0.01 mmol). After 10 min, phenylsilane (78 μl, 0.63 mmol) was added dropwise. After 3 days, the reaction mixture was concentrated and directly purified by flash chromatography on silica gel (AcOEt/hexane:30/70→50/50) to afford the title compound XVIIa as a yellow sticky oil.
Reaction SMILES: [CH:1]1([NH:8][C:9](=S)[NH:10][NH2:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[ClH:13].[CH:1]1([NH:8][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[NH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNC(=S)NC1CCCCCC1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(NC2CCCCCC2)n[nH]c1C
Product: Cl
Yield: 55.1 %

Procedure:
A solution of 11.6 g (0.0619 mole) of 4-cycloheptyl-3-thiosemicarbazide in 100 mL of tetrahydrofuran was stirred under nitrogen atmosphere while 10.2 g (0.062 mole) of ethyl 2-chloroacetoacetate was added. The reaction mixture quickly turned yellow and slowly became exothermic to boiling. The reaction mixture was refluxed for 1.5 hr, filtered (to remove amorphous sulfur), and concentrated in vacuo to give a yellow granular solid, 19.7 g. Several attempts at recrystallization of the material from various solvents resulted in 4 fractions all having melting points in the range of 157°-160° C. These were combined (12 g) and recrystallized from methyl isobutyl ketone, after treating with charcoal, to give 10.3 g of product. After drying at 82° C. under vacuum for 15 hr the weight was reduced to 9.8 g with mp 155°-161° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][NH:14][C:15]([C:17]2[N:18]=[C:19]3[C:25]([CH3:27])([CH3:26])[NH2+:24][CH2:23][CH2:22][CH2:21][N:20]3[C:28](=[O:31])[C:29]=2[OH:30])=[O:16])=[CH:11][CH:10]=1.C=O.C([BH3-])#N.[Na+]>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]([C:17]2[N:18]=[C:19]3[C:25]([CH3:27])([CH3:26])[N:24]([CH3:2])[CH2:23][CH2:22][CH2:21][N:20]3[C:28](=[O:31])[C:29]=2[OH:30])=[O:16])=[CH:32][CH:33]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC1(C)[NH2+]CCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Reactant: O=C([O-])C(F)(F)F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CN1CCCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1(C)C
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A methanolic solution of 2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-10,10-dimethyl-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a][1,4]diazepin-9-ium trifluoroacetate (prepared as described in Example 9, Step 1-2) was treated with formaldehyde (1.5 eq.) and sodium cyanoborohydride (1.2 eq.). The mixture was stirred at room temperature 3 hours and then directly purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) to give the title product as TFA salt, after lyophilization of the appropriate fractions.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[C@@H:8]([C@@H:16]([CH3:19])[CH2:17][CH3:18])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([CH2:31]O)[N:30]=2)[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[O:1]=[C:2]1[N:6]([CH2:31][C:29]2[N:30]=[C:26]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[S:27][CH:28]=2)[C:5](=[O:7])[CH2:4][N:3]1[C@@H:8]([C@@H:16]([CH3:19])[CH2:17][CH3:18])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: OCc1csc(-c2cccnc2)n1
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)NC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)N(Cc2csc(-c3cccnc3)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 36C (0.081 g, 0.30 mmol) in dichloromethane (2 mL) at 0° C. was treated with the product from Example 57A (0.063 g, 0.33 mmol), triphenylphosphine (0.103 g, 0.39 mmol), followed by diethyl azodicarboxylate (0.061 mL, 0.39 mmol), stirred at 25° C. for 16 hours. Water (3 mL) was added and the reaction was stirred for 2 hours at 25° C. The reaction mixture was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated, to give the crude product, which was used without further purification.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:25][NH:26][O:27][CH3:28].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH3:10])[C:11]([N:26]([O:27][CH3:28])[CH3:25])=[O:13])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CNOC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81.5 %

Procedure:
To a solution of Boc-alanine (20 grams, 105.7 mmol) in dichloromethane (170 ml) was added HOBT (14.28 g, 105.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.31 g, 105.7 mmol). The mixture was chilled with an ice water bath then triethylamine (30 ml, 211.4 mmol) and 1,3-dicyclohexylcarbodiimide (21.81 g, 105.7 mmol) were added. The reaction was stirred in the ice water bath for 1 hour and then allowed to warm to room temperature overnight. The crude reaction was then chilled in an ice water bath and the precipitate filtered. The resulting organic solution was then washed twice with 1N aqueous sodium hydroxide (50 mL), twice with 10% aqueous citric acid (50 mL), and once with brine. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 30-100% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (20 g, 81%): ES-MS (m/z) 233.2 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH:10]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:7][C:6]=1C)[CH3:3].N1CC(OC2C=CC([CH2:35][N:36]([CH3:38])[CH3:37])=C(C)C=2)C1.CN1CCNCC1.[Cl:47]C1C=C(O)C=CC=1C=O>>[NH:12]1[CH2:11][CH:10]([O:9][C:8]2[CH:21]=[CH:22][C:5]([CH2:4][N:2]3[CH2:1][CH2:37][N:36]([CH3:38])[CH2:35][CH2:3]3)=[C:6]([Cl:47])[CH:7]=2)[CH2:13]1
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN(C)C
Reactant: Cc1cc(OC2CNC2)ccc1CN(C)C
Reactant: O=Cc1ccc(O)cc1Cl
Agent: CN1CCNCC1
Product: CN1CCN(Cc2ccc(OC3CNC3)cc2Cl)CC1
Yield: 32 %

Procedure:
Using similar protocols as described in Examples 20A, 20B and 20C employing 1-methylpiperazine and 2-chloro-4-hydroxybenzaldehyde as starting material afforded 0.32 g (32%) of 49A as an oil. 1H NMR (500 MHz, CDCl3): δ 2.29 (s, 3H), 2.3-2.7 (m, 8H), 3.55 (s, 2H), 3.78 (m, 2H), 3.92 (m, 2H), 4.96 (m, 1H), 6.64 (d, 1H), 6.74 (d, 1H), 7.31 (m, 1H), MS (APCI+) m/z 296 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=3)=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:10]=2[C:9]1=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.[CH2:43](N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:43])[C:15]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=3)=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=4)(=[O:41])=[O:40])[CH:18]=3)[C:10]=2[C:9]1=[O:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(N)n3)c(-c3cccc(N)c3)c2C1=O
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Product: Cn1c2c(c(-c3cccc(NS(=O)(=O)c4cccc(F)c4)c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2

Procedure:
To a solution of 3-(3-amino-phenyl)-2-(2-amino-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetra-hydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (30 mg, 0.070 mmol) (prepared as described in Example 1) in dichloromethane (1 mL), 3-fluoro-benzene-sulfonyl chloride (0.010 mL, 0.077 mmol) and a drop of triethylamine were added. The mixture was stirred until disappearance of the starting material. The solvent was evaporated and the residue was suspended in diethylether and filtered to give 20 mg of 2-(2-amino-pyrimidin-4-yl)-3-[3-(3-fluoro-benzenesulfonylamino)-phenyl]-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. (y: 50%)