Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][C:12]([CH3:14])=O.N1CCCC1>CO>[CH3:11][C:12]1([CH3:14])[CH2:9][C:8](=[O:10])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:1]1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccccc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC1(C)CC(=O)c2ccccc2O1

Procedure:
A solution of 2′-hydroxyacetophenone (5.0 mL), acetone (4.7 mL), and pyrrolidine (5.4 mL) in 150 mL of methanol was stirred for 66 hours. The mixture was concentrated and treated with aqueous HCl (pH<1). The acidic layer was extracted twice with ethyl ether, which was dried and concentrated to provide 2,2-dimethylchroman-4-one. The 2,2-dimethylchroman-4-one was dissolved in 300 mL of methanol and treated with ammonium acetate (65 g) and sodium cyanoborohydride (2.5 g) for 24 hours. The resulting mixture was concentrated to 100 mL and diluted with 300 mL water. Concentrated HCl was carefully added until the pH was less than 1 and the acidic mixture was extracted with ethyl ether. The acidic phase was made basic with KOH and then extracted twice with ethyl ether. The basic extracts were dried and concentrated to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C@@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]([OH:46])[CH:37]=3)[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:48][CH:49]([CH3:51])[CH3:50].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]([CH2:25][C@@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]([O:46][CH2:48][CH:49]([CH3:51])[CH3:50])[CH:37]=3)[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)cc1O
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)cc1OCC(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of the compound of Example 181 (0.097 g, 0.0015 mmol, 1.0 eq.) in N,N-dimethylformamide (0.5 mL) were added 1-iodo-2-methylpropane (0.10 ml) and potassium carbonate (0.10 g). The reaction mixture was stirred at 60° C. for 16 hours. The mixture was diluted with distilled water (2 mL) and extracted with ethyl acetate (3×2 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as clear oil (0.076 g, 74%). LC-MS: 705.3 (MH+), retention time: 4.01 min.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60]([NH:62][C:63]2[CH2:66][N:65](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH:64]=2)=[O:61])[CH2:43]1>>[NH:65]1[CH2:66][CH:63]([NH:62][C:60]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][NH:45]2)=[O:61])[CH2:64]1
Reactant: O=C(NC1=CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)NC4CNC4)C3)[C@H](C)[C@H]12
Yield: 14.7 %

Procedure:
Following a procedure similar to that described in Example 121(1), followed by a procedure similar to that described in Example 49, but using 0.80 g of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and 0.95 g of (2S,4S)-4-mercapto-2-[1-(4-nitrobenzyloxycarbonyl)azetin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 33), 86 mg of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[Cl-].[NH4+].CCO>[Fe].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC1CCN(c2cc(Br)ccc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1CCN(c2cc(Br)ccc2N)CC1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
A flask charged with 1-(5-bromo-2-nitro-phenyl)-4-methyl-piperidine (1.0 g, 3.3 mmol) (as prepared in the previous step), ammonium chloride (1.8 g, 33 mmol), iron powder (0.93 g, 16 mmol), EtOH (12 mL) and water (6 mL) was heated at 80° C. for 1 h. The reaction was filtered though Celite, concentrated and eluted from a 20-g SPE cartridge (silica) with 100% DCM to give 0.80 g (91%) of the title compound as a yellow oil. Mass spectrum (ESI, m/z): Calcd. for C12H17BrN2, 269.1/271.1 (M+H), found 269.1/271.1.
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:17])([C:11](=[O:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[CH3:10])[C:5](=[O:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C>[Br:1][CH:14]([CH3:15])[CH2:13][CH2:12][C:11](=[O:16])[C:9]([N:6]1[C:5](=[O:18])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]([CH3:2])[O:8][CH2:7]1)([CH3:10])[CH3:17]
Reactant: Br
Reactant: C=CCCC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Solvent: CC(=O)O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CCC(C)Br)CO1
Reaction time: 5 h

Procedure:
Hydrogen bromide solution in acetic acid (50 g of 30% w/w) was added to 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-hept-6-en-3-one (4.14 g) and stirred for 5 hours. Evaporation and dry column chromatography on silica gel eluting with hexane/ethyl acetate (4:1) gave 6-bromo-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-heptan-3-one (1.04 g) as a brown gum, NMR 1.4(s,6H), 1.7(d,3H), l.9(m,1H), 1.9(s,3H), 2.2(m,1H), 2.7(m,2H), 4.1(m,1H), 5.3(s,2H), 7.3(m,5H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#N.[NH2:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16](Cl)[N:15]=1.C[N:23](C)C=O>>[C:9]([O:8][C:6](=[O:7])[CH2:5][C:3]1[C:18]([Cl:20])=[N:19][C:14]([NH2:13])=[N:15][C:16]=1[C:17]#[N:23])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: CN(C)C=O
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)Cc1c(Cl)nc(N)nc1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (17.6 g, 733 mmol) in dry N,N-dimethylformamide (DMF) at 0° C. was added dropwise t-butyl cyanoacetate (96 g, 680 mmol). The tan suspension was stirred at 0° C. for 0.5 hours then 2-amino-4,6-dichloropyrimidine (58.7 g, 358 mmol) was added batchwise. The mixture was heated slowly to 90° C. and the reaction was held at 90° C. for 18 hours. The reaction mixture was poured onto water (1 l) and the mixture was filtered. The filtrate was acidified with con HCl to pH 6 and the resultant solid was filtered and washed with water and hexanes and dried to furnish 99.64 g of the desired subject as a green powder, m.p. 107°-109° C. NMR (200 mHz) D6-acetone δ 12.8 (bs, 1 H), 8.0 (bs, 1 H), 7.8 (bs, 1 H), 6.3 (s, 1 H), 1.5 (s, 9 H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][CH2:13][C:14]([OH:31])([CH3:30])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=2)=[O:16])=[CH:4][CH:3]=1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:37].[OH2:47]>ClCCl.[Cl-].[Na+].O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([CH2:13][C:14]([OH:31])([CH3:30])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:19]=2)=[O:16])(=[O:37])=[O:47])=[CH:4][CH:3]=1
Reactant: CC(O)(CSc1ccc(Br)c2ccccc12)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(CS(=O)(=O)c1ccc(Br)c2ccccc12)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(1-bromonaphthalen-4-ylthio)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (13 mg, 0.025 mmol) in dichloromethane (0.06 mL) at −78° C. was added 30% hydrogen peroxide (4.4 μL, 0.155 mmol) followed by the slow addition of trifluoroacetic anhydride (18 μL, 0.13 mmol). The reaction was stirred at room temperature for 16 h before the reaction was diluted with dichloromethane. Cold water and brine were added, and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 9 mg of desired product.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([C:19]2[CH:29]=[CH:28][C:22]3[N:23]([CH3:27])[C:24](=[O:26])[O:25][C:21]=3[CH:20]=2)=[O:18])=[C:12]([Cl:31])[CH:11]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([C:19]2[CH:29]=[CH:28][C:22]3[N:23]([CH3:27])[C:24](=[O:26])[O:25][C:21]=3[CH:20]=2)([OH:18])[C:2]([F:4])([F:3])[F:1])=[C:12]([Cl:31])[CH:11]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C(=O)c1ccc2c(c1)oc(=O)n2C)c1ccc(Br)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)oc(=O)n2C)C(F)(F)F
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Trifluoromethyltrimethylsilane (2M in THF, 1.48 mL) was added at 0° C. to a solution of 6-[2-(4-bromo-2-chloro-phenyl)-propionyl]-3-methyl-3H-benzooxazol-2-one (531 mg) in THF (15 mL) followed by the addition of tetrabutylammonium fluoride trihydrate (424 mg). Stirring was continued for 48 hours at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=7:3) to give the title compound as a orange amorphous foam (440 mg, 70%). MS (neg. ion, m/e)=464.0 [(M−H)−].
Reaction SMILES: C([O:5][CH:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]#[N:13])[CH2:7]1)(=O)CC.[OH-].[Na+].Cl>C1COCC1.CCO>[OH:5][CH:6]1[CH2:7][C:8]([C:12]#[N:13])=[CH:9][CH2:10][CH2:11]1
Reactant: CCC(=O)OC1CCC=C(C#N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: N#CC1=CCCC(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R or S)-3-cyanocyclohex-3-en-1-yl propanoate (210 g, 1.17 mol) in 1:1 THF/EtOH (2 L) at 0° C. was added 3M aqueous NaOH (586 mL, 1.76 mol) dropwise via addition funnel over 30 minutes. After addition, The mixture was stirred at ambient temperature for 2 hours. The mixture was carefully neutralized with 3N aqueous HCl (195 mL), concentrated to remove most of the THF/EtOH. The resulting mixture was diluted with brine (1.5 L) and extracted with EtOAc (1.2 L, then 600 mL×4). The combined organics were washed with brine (200 mL×2). The aqueous layer was back-extracted with EtOAc (200 mL×2), and the combined organic extracts were dried over anhydrous Na2SO4, and concentrated in vacuo to give the enantioenriched title compound (chiral HPLC: 98.4% ee). 1H NMR data was consistent with that reported in the literature for racemic 5-Hydroxycyclohex-1-enecarbonitrile.
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[NH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1>C(O)(=O)C>[C:26]([O:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([N:18]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:2]2[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:31][CH:30]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(O)CCC(=O)CCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(-n2c(CCC(=O)O)ccc2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 59 %

Procedure:
To a stirred solution of 4,7-dioxo-7-phenyl-heptanoic acid (3.57 mmol, 1.0 eq.) in acetic acid (10 ml) was added tert-butyl 4-aminobenzoate (1.05 eq., 3.75 mmol). The mixture was heated to 80° C. for 36 hours. The solvent was evaporated in vacuo and the crude residue purified by flash silica-gel chromatography. Gradient elution with ethyl acetate/hexane (0% to 50% ethyl acetate in hexane over 20 minutes) gave the semi-pure product after combination of the appropriate fractions and evaporation of the solvent in vacuo. The tan solid obtained was used without further purification, 59% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][O:28]C2CCCCO2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][OH:28])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
4.1 g 2-Chloro-4-[4-(tetrahydro-pyran-2-yloxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile were dissolved in 50 ml methanol. 320 mg p-toluenesulfonic acid monohydrate were added and the mixture was stirred for one hour at room temperature. The solvent was removed in vacuo and the residue was dissolved in ethylacetate and washed twice with saturated NaHCO3 solution and brine then dried over MgSO4. The solvent was removed in vacuo to obtain 3.4 g 2-Chloro-4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([O:22][C:23](=[O:44])[N:24]([CH3:43])[CH2:25][C@H:26]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)[CH3:27])([CH3:21])([CH3:20])[CH3:19]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:31]1[CH:30]=[CH:29][C:28]([C@H:26]([CH3:27])[CH2:25][N:24]([CH3:43])[C:23](=[O:44])[O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:33][CH:32]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Yield: 49 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (2.5 g, 8.1 mmol) was reacted with (S)-tert-butylmethyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)carbamate (4.6 g, 12 mmol) to afford the desired product (1.9 g, 50%) as a light brown solid: ESI MS m/z 47 [C27H30N2O4S+H]+.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[N:19]=[N:20][C:21]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:22][CH:23]=2)=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:21]2[N:20]=[N:19][C:18]([CH2:17][C:10]3[C:11]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:8][CH:9]=3)=[CH:23][CH:22]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)n1cc(Cc2ccc(NCc3ccc(Cl)cc3)nn2)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncccc34)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-[6-(4-chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (523, 50.0 mg, 0.111 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at room temperature overnight. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give an off-white solid (P-0092, 7.3 mg, 19.0%). MS (ESI) [M+H+]+=350.1.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:40][CH2:41][N:42]([CH2:45][CH2:46][O:47][C:48]([C:50]1[CH:51]=[CH:52][C:53]([NH2:56])=[CH:54][CH:55]=1)=[O:49])[CH2:43][CH3:44].Cl>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:14]4[CH2:20][CH2:19][CH:18]3[CH2:17][O:16][CH2:15]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH:25][C:29]([NH:56][C:53]4[CH:54]=[CH:55][C:50]([C:48]([O:47][CH2:46][CH2:45][N:42]([CH2:41][CH3:40])[CH2:43][CH3:44])=[O:49])=[CH:51][CH:52]=4)=[O:31])=[CH:23][CH:22]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Reactant: CCN(CC)CCOC(=O)c1ccc(N)cc1
Agent: Cl
Product: CCN(CC)CCOC(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4C5CCC4COC5)n3)cc2)cc1
Yield: 38.6 %

Procedure:
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and procaine hydrochloride (50 mg, 0.18 mmol) gave the title compound as off-white solid (1TFA salt, 14.6 mg, 33% yield). MS (ESI) m/z 613.6.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH3:12][C:13]1[N:18]=[C:17]([C:19]2[C:20](B(O)O)=[C:21]3[CH2:26][CH2:25][CH2:24][N:22]3[N:23]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH3:12][C:13]1[N:18]=[C:17]([C:19]2[C:20]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[N:7][CH:6]=[CH:5]4)=[C:21]3[CH2:26][CH2:25][CH2:24][N:22]3[N:23]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Ic1ccc2cnccc2c1
Reactant: Cc1cccc(-c2nn3c(c2B(O)O)CCC3)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4cnccc4c2)CCC3)n1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
Dissolve 6-iodoisoquinoline (0.085 g, 0.333 mmol) and 2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 2; 0.077 g, 0.317 mmol) in dioxane (2.5 mL). Add 5M aqueous potassium carbonate (0.667 mL, 3.33 mmol) followed by triphenylphosphine (5.2 g, 0.020 mmol) and tris(dibenzylidineacetone)dipalladium (18 mg, 0.020 mmol). Reflux the mixture for 2 h and cool to room temperature. Load the reaction mixture on to a cartridge containing SCX resin (5 g) and wash the resin sequentially with 1 volume dichloromethane, 1 volume methanol, and 1 volume methanol containing 2N ammonia. Remove the organic solvents under reduced pressure. Chromatograph on 15 g silica gel eluting with 5% methanol in ethyl acetate to provide 0.053 g (48%) of the title compound as a tan solid.
Reaction SMILES: [C:1]([C:5]1O[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:13]>>[C:1]([C:5]1[NH:13][CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)c1cc(=O)cco1
Agent: [OH-]
Product: CC(C)(C)c1cc(=O)cc[nH]1

Procedure:
A mixture of 2-tert-butyl-pyran-4-one (Step 1.6) (5.74 g, 37.7 mmol) and a 30% aqueous solution of ammonium hydroxide (100 mL) is stirred for 1 h at reflux, allowed to cool and concentrated. The residue is triturated with MeOH (200 mL) and filtered. The filtrate is concentrated and the residue purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1→92:7:1) to afford 4.46 g of the title compound as a yellow solid: ESI-MS: 152.0 [M+H]+; tR=1.45 min (System 1); TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:8]=2[CH:21]=1)([OH:3])=O.[C:22]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[C:22]1([S:28]([NH:31][C:1]([C:4]2[CH:5]=[CH:6][C:7]3[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:20])[C:8]=3[CH:21]=2)=[O:3])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
N,N'-carbonyldiimidazole (45.8 g) was added at a time to a solution of 45.0 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 950 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, 47.1 g of benzenesulfonamide and 35.0 g of diazabicycloundecene were added thereto, and the mixture was stirred at 100° C. for 70 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. To the residue were added 300 ml of water and 200 ml of methanol. Further, 60.7 g of 35% hydrochloric acid were added thereto to adjust the solution to a pH of 5.5. The crystals precipitated were separated through filtration, washed with 200 ml of a mixed solution of methanol and water (at a ratio of 1:1), and dried to obtain 38.4 g of 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole. Water was added to the filtrate. The crystals precipitated were separated through filtration, washed with water, and dried. The amount of the crystals was 13.3 g. The crystals were combined, and were dissolved by being heated with the addition of 3300 ml of acetone and 900 ml of water. From this solution, 200 ml of the solvent were distilled off while being heated, and the residue was cooled. The crystals precipitated were separated through filtration, and were dried to give 33.8 g of 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole (163).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.Cl>C(O)(C)C>[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:18][CH:16]([OH:17])[CH2:15][O:14][C:13]3[C:3]([O:2][CH3:1])=[CH:4][C:5]4[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=4[CH:12]=3)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc2oc(=O)ccc2cc1OCC1CO1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2oc(=O)ccc2cc1OCC(O)CN1CCN(c2cccc(Cl)c2)CC1
Yield: 85 %

Procedure:
Method C (3 d at 40° C.); starting materials: 7-methoxy-6-(oxiranylmethoxy)-2H-1-benzopyran-2-one and 1-(3-chlorophenyl)-piperazine; yield 85%; fusion point 140°-141° C. (from isopropanol). Hydrochloride (×1.7 HCl): method F; yield 88%; fusion point 222°-224° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[CH2:29][CH:30]=O>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[C:29]1[CH:30]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: O=CCc1c(Cl)cccc1Cl
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Oc1cccc(-c2c(-c3c(Cl)cccc3Cl)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2,6-dichloro-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 431.8; HRMS: calcd for C22H12Cl2F3NO+H+, 434.03208; found (ESI, [M+H]+), 434.033.