Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: COc1ccc2c(c1CCCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CCCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)butyl]piperidine-1-carboxylate (0.0483 g, 0.119 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0174 g, 0.119 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate), and the resulting crude product was purified again by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}butyl)piperidine-1-carboxylate (0.0454 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:15][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]
Reactant: CC(C)=CCBr
Reactant: Cc1ccc(Nc2ccccn2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ccccn2)ccc1C
Yield: 48 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-methyl-5-(pyridin-2-ylamino)phenol (67 mg, 0.33 mmol) and Cs2CO3 (113 mg, 0.35 mmol) in acetone (3.3 mL) was treated with 4-bromo-2-methyl-2-butene (0.038 mL, 0.33 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 48% yield (43 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:11]([O-])=O)=[C:5]([NH:9][CH3:10])[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH3:10])[C:4]=1[NH2:11]
Reactant: CNc1cccc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1cccc(OC)c1N
Reaction time: 4.5 h
Yield: 95.4 %

Procedure:
7.4 g (3-methoxy-2-nitrophenyl)-methylamine are suspended in 150 ml of ethyl acetate and hydrogenated with 1 g Pd/C 10% at a pressure of 50 psi and at ambient temperature. After 4.5 hours the catalyst is suction filtered and the filtrate is evaporated to dryness. 5.9 g of the product are obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:8]3[C:9]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[N:26][OH:27])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.COC1C=CC2[C:35]3[C:36](N4CCNCC4)=[N:37]C4C([C:34]=3C(=O)C=2C=1)=CC=CC=4.C(C1OC1)Cl>>[NH2:37][CH2:36][CH2:35][CH2:34][O:27][N:26]=[C:6]1[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:8]=2[C:23]2[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]1=2
Reactant: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Reactant: COc1ccc2c(c1)C(=NO)c1c-2c(N2CCNCC2)nc2ccccc12
Solvent: ClCC1CO1
Product: COc1ccc2c(c1)C(=NOCCCN)c1c-2c(N2CCNCC2)nc2ccccc12

Procedure:
9-Methoxy6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one O-3-aminopropyl oxime (6t) was prepared substantially according to the procedures as set forth in the above Synthesis Example 18, except that compound 6p and 3-bromopropylamine·Br were used in place of compound 5x and epichlorohydrin, respectively, giving the title compound at a yield of 41%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:24])[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1.FC(F)(F)C(O)=O.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)Cl>[CH3:12][C:13]1([CH3:24])[C:22](=[O:9])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1
Reactant: CC1(C)C=Cc2cc(F)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Oc2ccc(F)cc2CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40.6 g (0.2 mol) of m-chloroperbenzoic acid are added, while stirring at from 15° to 20°, to a solution of 17.8 g (0.1 mol) of 2,2-dimethyl-6-fluoro-2H-chromene in 300 ml of trichloromethane. 17.1 g (0.15 mol) of trifluoroacetic acid are added rapidly to the resulting suspension at room temperature. The reaction mixture is then stirred at room temperature for 2 hours and then an aqueous solution of sodium sulfite/sodium hydrogen carbonate (1:1) is added thereto. The organic phase is separated off, washed in succession with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The resulting residue is subjected to bulb tube distillation under a high vacuum at 160°. The distillate is dissolved in diethyl ether and the solution is washed in succession with sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and again concentrated by evaporation in vacuo. The resulting oily residue is chromatographed on 500 g of silica gel (0.040- 0.063 mm) with toluene as eluant, yielding 7.76 g (40% of the theoretical yield) of 2,2-dimethyl-6-fluoro-3-oxo-chroman in the form of a light-yellow oil.
Reaction SMILES: C([NH:8][C@@:9]1([CH3:27])[C@@H:16]2[C@@H:12]([CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH2:15]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)(C)C>[CH3:27][C@:9]1([NH2:8])[C@@H:16]2[C@@H:12]([CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH2:15]2)[CH2:11][CH2:10]1
Reactant: C[C@@]1(NCc2ccccc2)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: [H][H]
Solvent: CC(C)O
Product: C[C@@]1(N)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21

Procedure:
(3aR,4R,6aS)—N-Benzyl-4-methyl-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-amine (30 mg, 0.080 mmol) from Example 21 and isopropanol (14 mL) were added to 20% Pd(OH)2—C, wet (6.0 mg, 0.043 mmol) in a 50 mL pressure bottle and stirred for 90 minutes under 30 psi hydrogen gas at 50° C. The mixture was filtered through a nylon membrane and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.54-7.46 (m, 1H), 6.97 (d, J=7.2, 1H), 6.52 (d, J=8.6, 1H), 3.75 (dd, J=11.3, 5.2, 1H), 3.56 (dd, J=10.3, 8.4, 1H), 3.52-3.43 (m, 1H), 3.36 (dd, J=10.5, 3.9, 1H), 2.72-2.62 (m, 1H), 2.31 (td, J=8.7, 5.3, 1H), 1.92-1.81 (m, 1H), 1.77-1.68 (m, 1H), 1.60-1.35 (br m, 2H), 1.54-1.42 (m, 2H), 1.16 (s, 3H); MS (ESI+) m/z 286 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC[O:14][CH:15](Cl)[CH3:16])C.Cl[Si](C)(C)C.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24].CN(C)C=[O:32]>O>[OH:25][CH:23]([O:26][CH2:27][CH2:28][O:14][CH:15]([OH:32])[CH3:16])[CH3:24]
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Reactant: CC(Cl)OCCOC(C)Cl
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(O)OCCOC(C)O
Reaction time: 0.5 h

Procedure:
The thus obtained partially hydroxycarbonylmethylated polyhydroxystyrene, 90 g, was dissolved in 180 g of N,N-dimethylformamide. With stirring under ice cooling, 40.5 g of triethylamine and then 1.7 g of ethylene glycol di(1-chloroethyl) ether were added. Reaction was carried out for 30 minutes under ice cooling, 24.2 g of chlorotrimethylsilane was added, and reaction was carried out for a further 2 hours at room temperature. To the reaction mixture were added 500 g of ethyl acetate and 300 g of water, followed by separation. The ethyl acetate layer was washed twice with 300 g of water and then concentrated in vacuum. The residue was dissolved in 300 g of methanol and added dropwise to 20 liters of water whereupon a powdery solid precipitated. The solid was collected by filtration, washed with 20 liters of water, and dried in vacuum at 40° C. for 24 hours. On 1H-NMR analysis, it was identified to be a polymer (Polym. 9) in which 25.0 mol % of the hydrogen atoms of hydroxyl groups in polyhydroxystyrene were replaced by trimethylsilyl groups, and the carboxyl group moieties which had been introduced in an amount of 2.0 mol % formed ester bonds with alcoholic hydroxyl groups of ethylene glycol di(1-hydroxyethyl) ether to provide crosslinking.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]=[N:4][C:5]1[CH:6]=[CH:7][C:8]([C:15]([O:17][CH3:18])=[O:16])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([NH:30][C:31](OC2C=CC=CC=2)=[O:32])[N:23]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([O:21][CH3:20])[N:23]=[C:24]([NH:30][C:31]([NH:14][S:11]([C:9]2[CH:10]=[C:5]([N:4]=[CH:3][N:2]([CH3:19])[CH3:1])[CH:6]=[CH:7][C:8]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:13])=[O:12])=[O:32])[N:25]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)c1ccc(N=CN(C)C)cc1S(N)(=O)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc(N=CN(C)C)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C

Procedure:
A suspension of 1.50 g of 5-(2-dimethylamino-1-azaethenyl)-2-methoxycarbonylbenzenesulfonamide, 1.61 g of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine, 32 ml of acetonitrile and 0.83 ml of DBU is stirred initially at 0° C. and then at room temperature until the reaction has ended. The reaction mixture is then concentrated under reduced pressure. The residue is taken up in water and washed with diethyl ether. The aqueous phase is carefully acidified with conc. hydrochloric acid (pH 6) and the sulfonylurea precipitate is separated off, washed with diisopropyl ether and water and dried. This affords 1.89 g of the desired sulfonylurea, melting point 73-75° C.;
Reaction SMILES: C(C1[C:4](F)=[CH:5][C:6]2[N:12]=[C:11]([N:13]([CH3:15])[NH2:14])[CH:10](C(C)C)[N:9]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25]CCC)[C:7]=2[CH:29]=1)C.C(N(CC)CC)C.O1CCCC1.[C:43](Cl)(Cl)=[S:44].[CH2:47]([Cl:49])Cl.CO>>[OH-:25].[Cl:49][C:47]1[CH:4]=[CH:5][C:6]2[N:12]3[C:43]([SH:44])=[NH+:14][N:13]([CH3:15])[CH:11]3[CH2:10][N:9]=[C:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:7]=2[CH:29]=1
Reactant: CCCOc1ccccc1C1=NC(C(C)C)C(N(C)N)=Nc2cc(F)c(CC)cc21
Reactant: S=C(Cl)Cl
Reactant: ClCCl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1[NH+]=C(S)N2c3ccc(Cl)cc3C(c3ccccc3)=NCC12
Product: [OH-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 4.48 g. (0.015 mole) of 7-chloro-2-(1-methylhydrazino)-5-phenyl-3H-1,4-benzodiazepine (III), (prepared as in Example 1), 4.68 ml. (0.033 mole) of triethylamine and 60 ml. of tetrahydrofuran is cooled, under nitrogen, in a salt bath, and treated dropwise during about 1 hour and 20 minutes with a solution of 1.26 ml. of thiophosgene in 30 ml. of tetrahydrofuran. The mixture is allowed to warm slowly to room temperature, stand for about 16 hours and heated under reflux for about 70 minutes. The mixture, after cooling, is poured into ice water, the solid collected by filtration, dissolved in chloroform, washed with brine and dried with sodium sulfate. The aqueous filtrate is concentrated under vacuum to remove tetrahydrofuran and then extracted with chloroform. The extract is washed with brine and dried with sodium sulfate. The chloroform solutions are combined and concentrated and the residue chromatographed on 300 g. of silica gel with 2% methanol-98% chloroform. The product thus obtained is recrystallized from a mixture of methylene chloride and methanol to give a first crop weighing 1.33 g. with a melting point of 261.5° to 267° C. (with decomposition) and a second weighing 1.94 g. with a melting point of 258° to about 267° C. (with decomposition) with softening at 245° C. These two samples are apparently different polymorphic crystalline forms since they have different solubility in methylene chloride-methanol, different infrared (ir) (Nujol) absorption spectra but identical ultraviolet (uv) (EtOH) absorption spectra and nuclear magnetic resonance (nmr) (DMSO) spectra. They also show the same empirical formulae by elemental and mass spectral analysis. The second crop is recrystallized twice from methylene chloride-methanol for analysis. The analytical sample of this crop of the product, 8-chloro-1-mercapto-3-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepinium hydroxide inner salt (IV), has a melting point of 258° to 262° C. (with decomposition) with softening at 245° C.; uv (EtOH) λmax. 219.5 mμ (ε=46,100), 245 (shoulder 19,150), 260 (sh 11,250), 278 (sh 8250), 310 (sh 4200). The ir, nmr and mass spectra of the compound support its proposed structure.
Reaction SMILES: O(Cl)Cl.[Cl:4][CH2:5][CH3:6].[C:7]([Cl:11])(Cl)([Cl:9])[Cl:8]>>[Cl:4][CH:5]([Cl:8])[CH3:6].[Cl:8][C:7]([Cl:11])([Cl:9])[CH3:5]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCCl
Agent: ClOCl
Product: CC(Cl)(Cl)Cl
Product: CC(Cl)Cl

Procedure:
Kochanny et al., in U.S. Pat. No. 3,872,176, disclose reaction of Cl2O with 1-chloroethane alone or in CCl4 at 0° to 40° C. to give predominantly 1,1-dichloroethane and 1,1,1-trichloroethane;
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[C:3]=1[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:37][CH:38]([CH3:40])[CH3:39])=[C:33]([CH:36]=1)[C:34]#[N:35]>CN(C=O)C>[C:34]([C:33]1[CH:36]=[C:29]([CH:30]=[CH:31][C:32]=1[O:37][CH:38]([CH3:40])[CH3:39])[CH2:28][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[C:3]=1[CH3:20])#[N:35]
Reactant: CCOC(=O)CC1CCn2c1cc1c(C)c(O)ccc12
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCn2c1cc1c(C)c(OCc3ccc(OC(C)C)c(C#N)c3)ccc12
Temperature: 65 °C
Yield: 79.5 %

Procedure:
To a solution of ethyl 2-(7-hydroxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (100 mg, 0.366 mmol) in DMF (3 mL) was added cesium carbonate (155 mg, 0.476 mmol), followed by 5-(chloromethyl)-2-isopropoxybenzonitrile (100 mg, 0.476 mmol). The reaction mixture was heated at 65° C. for 15 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by column chromatography to give the title compound (130 mg) as a colorless oil. LCMS m/z=447.7 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 1.42 (d, J=6.0 Hz, 6H), 2.25-2.32 (m, 1H), 2.42 (s, 3H), 2.58 (dd, J=16.0, 8.4 Hz, 1H), 2.82-2.92 (m, 2H), 3.73-3.80 (m, 1H), 3.95-4.02 (m, 1H), 4.08-4.15 (m, 1H), 4.20-4.27 (m, 2H), 4.62-4.69 (m, 1H), 4.96 (s, 2H), 6.13 (s, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.6, 2.2 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[O:1][C:13](=[O:14])[N:12]([CH3:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1nc2ccccc2[nH]1
Product: CN(C(=O)Oc1nc2ccccc2n1C(=O)N(C)c1ccccc1)c1ccccc1

Procedure:
The title product was prepared from 2-hydroxybenzimidazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (14%, white crystals). HPLC-MS: m/z=401.2 (M+1); Rt: 3.88 min, purity: 83%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:5]2=[CH:4][CH:3]=1.C[N:15]1[CH2:20]COCC1.O.[NH2:22]N.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]3[O:13][CH:20]=[N:15][N:22]=3)[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc2[nH]c(-c3nnco3)cc2n1
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
To 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (2.00 g, 10.2 mmol, from Example 99, Step 1) in THF (40 mL) at 0° C. was added 4-methylmorpholine (1.3 mL, 12 mmol, Aldrich) and isobutyl chloro formate (1.38 mL, 10.7 mmol, Aldrich). After 20 minutes, hydrazine hydrate (3.0 mL, 61 mmol, Aldrich) was added. Cooling was discontinued and the reaction was stirred overnight. The reaction mixture was diluted with EtOAc and washed sequentially with an additional NaHCO3 and brine. The aqueous layer was extracted with EtOAc. Insoluble material at the interface of the layers was collected by filtration. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product from the extracts and the solid from the filtration were combined and dissolved in trimethylorthoformate (35 mL, Aldrich). p-Toluenesulfonic acid (150 mg, 0.87 mmol, Aldrich) was added and the mixture was heated to 90° C. for 2 hours. Trimethylorthoformate was removed from the filtrate in vacuo to yield a crude product which was used in step 2 without purification.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.Cl.[CH3:25][C:26]([NH2:35])([CH3:34])[CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[CH3:34][C:26]([NH:35][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:25])[CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)(N)CN1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CN1CCOCC1
Temperature: 160 °C
Yield: 29 %

Procedure:
A mixture of 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (40 mg, 0.13 mmol), 2-methyl-1-morpholinopropan-2-amine dihydrochloride [prepared according to the procedures reported in US 20060035903 A1 (2006)] (62 mg, 0.27 mmol) and DIPEA (0.14 mL, 0.81 mmol) in DMSO (2 mL) in a sealed glass tube was heated at 160° C. in a microwave for 45 min. It was diluted with 50 mL of EtOAc, washed with 5 mL of sat. NaHCO3 followed by 5 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (3% MeOH in DCM followed by 3-10% of 2 M NH3 in MeOH in DCM) to provide the title compound (17 mg, 29% yield) as a yellow off white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (1H, br.), 7.79 (1H, dd, J=7.4, 1.2 Hz), 7.60 (1H, dd, J=8.0, 1.2 Hz), 7.35 (1H, t, J=7.7 Hz), 7.02 (1H, s), 6.96 (1H, s), 6.32 (1H, s), 3.60 (4H, m), 3.44 (2H, td, J=6.9, 2.2 Hz), 3.30 (4H, m), 2.86 (2H, t, J=6.8 Hz), 2.70 (2H, s), 2.58 (3H, s), 1.55 (6H, s). m/z (ESI, +ve) 435.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:39])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:16]=[C:15]([N:25]3[CH2:31][CH:30]4[O:32][CH:27]([CH2:28][CH2:29]4)[CH2:26]3)[N:14]=2)[C:11]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:39][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21][CH2:20]3)[N:16]=[C:15]([N:25]3[CH2:31][CH:30]4[O:32][CH:27]([CH2:28][CH2:29]4)[CH2:26]3)[N:14]=2)[C:11]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:10]=2[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CC3CCC(C2)O3)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCN(S(C)(=O)=O)CC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.5 %

Procedure:
Methanesulfonyl chloride (0.12 mL, 1.55 mmol) was added dropwise to a stirred suspension of 3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-8-oxa-3-azabicyclo[3.2.1]octane (165 mg, 0.349 mmol) and powdered K2CO3 (434 mg, 3.15 mmol) in CH2Cl2 (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 days. Water was added, the phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4) and the solvent removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (99:1), followed by recrystallization from CH2Cl2/MeOH gave 170 mg (89% yield) of 3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane: mp (CH2Cl2/MeOH) 312-314° C.; 1H NMR (CDCl3) δ7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.45 (t, JHF=53.6 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.49 (br s, 2H), 4.32 (d, J=13.2 Hz, 2H), 4.05 (s, 3H), 4.02 (br s, 4H), 3.30 (m, 6H), 2.81 (s, 3H), 1.99 (m, 2H), 1.79 (m, 2H); Anal. Calcd. for C23H28F2N8O4S: C, 50.2; H, 5.1; N, 20.35. Found: C, 50.3; H, 5.1; N, 20.5.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C[O-].[Na+].Cl[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.Cl>CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9])[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1
Reactant: ClCc1c[nH]cn1
Reactant: Cc1cccc(C)c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(Cc2c[nH]cn2)cc(C)c1O
Yield: 54 %

Procedure:
To a solution of 12.2 g of 2,6-dimethylphenol in methanol are added 20 ml of 30% sodium methoxide solution, and the resultant mixture is warmed to 50° C. The mixture is maintained at that temperature while 5.8 g of 4-chloromethylimidazole in methanol are added, with stirring. After the addition is complete, the reaction mixture is stirred at 50°-60° C. for about 4 hours, then is cooled and poured into cold water. That mixture is acidified with hydrochloric acid and washed with ethyl acetate. The pH of the aqueous solution is then adjusted to 7-8, and the product is obtained by extraction with ethyl acetate. The desired 4-(3',5'-dimethyl-4'-hydroxybenzyl)imidazole is obtained in 54% yield. The free base is converted to the corresponding hydrochloride salt by treatment with HCl in a mixture of ethyl acetate and isopropanol. That salt melts at 210°-214° C.