Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18](Cl)=[O:19].[OH-].[Na+]>ClCCCl.CO>[Cl:14][C:15]1[CH:16]=[C:17]([C:18]([C:3]2[C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[NH:1][CH:2]=2)=[O:19])[CH:21]=[CH:22][N:23]=1
Reactant: c1cc2[nH]ccc2cn1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: O=C(c1ccnc(Cl)c1)c1c[nH]c2ccncc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 122 %

Procedure:
To a solution of 1H-pyrrolo[3,2-c]pyridine (17.0 g, 0.14 mol) in 1, 2-dichloroethane (500 mL) was added AlCl3 (38.3 g, 0.29 mol) at room temperature. The mixture was stirred at room temperature for 10 minutes. A solution of 2-chloroisonicotinoyl chloride (30.0 g, 0.17 mol) in 1, 2-dichloroethane (100 mL) was added and the reaction heated to 70° C. Further AlCl3 (38.3 g, 0.29 mol) was added and the reaction was stirred at this temperature for 18 hours. The mixture was cooled to room temperature, and then to the mixture was added MeOH (150 mL) dropwise. 1M aqueous NaOH solution was added until pH=8. The mixture was filtered, the filter cake was washed with a mixture of 1/3 isopropanol/chloroform and the filtrate was extracted with a mixture of 1/3 isopropanol/chloroform (300 mL×6). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (44 g) as a black solid, which was used in next step directly.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH:27](OCC)[O:28]CC)[CH:22]=2)=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH:27]=[O:28])[CH:22]=2)=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(OCC)c1cc(C(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1cc(C(=O)NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Temperature: 50 °C

Procedure:
To a solution of 4-{[(2-diethoxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (1.3 g, 0.0029 mol) in dioxane (20 mL) was added 1N hydrochloric acid (40 mL) and the mixture was warmed to 50° C. for 1.5 h. The reaction was cooled, diluted with ethyl acetate (100 mL) and 10% aqueous sodium bicarbonate (100 mL), and stirred well. The organic layer was removed, dried over sodium sulfate, filtered and concentrated in vacuo to give 4-{[(2-formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester as an oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)=[CH:12][CH:11]=1.O>C(Cl)Cl>[Br:1][C:20]1[C:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)=[N:17][NH:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(-c2cc[nH]n2)cc1
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(-c2n[nH]cc2Br)cc1
Reaction time: 0.17 h

Procedure:
N-Bromosuccinimide (10.4 g, 56.0 mmol) was added portionwise to a solution of 3-(4-chlorophenyl)-1H-pyrazole (10.0 g, 56.0 mmol) in CH2Cl2 (140 mL). The mixture was stirred for 10 min, water and an additional portion of CH2Cl2 were added and the mixture was stirred for 5 min. The organic phase was separated, washed with brine, dried (MgSO4) and concentrated to yield 15.0 g of Ex 3-Step 1 product as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.6, 2H), 7.59 (s, 1H), 7.35-7.39 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[OH-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([S:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:24])=[O:23])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1cnc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of tetrabutylammonium bromide (154 mg, 0.48 mmol) and 1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (2.8 g, 15.9 mmol) in dichloromethane (40 mL) was added sodium hydroxide powder (1.9 g, 47.7 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min. Benzene sulfonyl chloride (3 mL, 23.8 mmol) was added slowly to the above mixture at 0° C. and the resulting mixture was stirred at 0° C. for another 15 min before it was warmed to 25° C. and kept at that temperature for 12 h. The reaction mixture was filtered and then concentrated in vacuo to afford 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester as a light yellow solid which was washed with hexane to give a white solid (4.6 g, 90%): 1H NMR (400 MHz, CDCl3) δ ppm 3.95 (s, 3H), 6.69 (d, J=4.0 Hz, 1H), 7.51 (m, 2H), 7.61 (m, 1H), 7.82 (d, J=4.0 Hz, 1H), 8.22 (m, 2H), 8.51 (d, J=2.0 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H).
Reaction SMILES: CN(C=O)C.[CH2:6]([C:9]1[C:17]2[O:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31])[CH2:7][CH3:8].[H-].[Na+].Br[CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37]>C(OCC)(=O)C>[O:31]=[C:27]1[N:26]([CH2:25][CH2:24][CH2:23][O:22][C:10]2[CH:11]=[CH:12][C:13]3[C:14]([C:18]([F:21])([F:19])[F:20])=[N:15][O:16][C:17]=3[C:9]=2[CH2:6][CH2:7][CH3:8])[CH2:30][CH2:29][N:28]1[CH:35]([CH3:40])[C:36]([O:38][CH3:39])=[O:37]
Reactant: CCCc1c(OCCCN2CCNC2=O)ccc2c(C(F)(F)F)noc12
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCN2CCN(C(C)C(=O)OC)C2=O)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a DMF solution (2 mL) of 1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one as prepared in Example 39 (10 mg, 0.027 mmol), was added NaH (4.3 mg, 1.08 mmol) and stirred at room temperature for 30 minutes. Methyl 2-bromopropionate (27 mg, 0.16 mmol) was added and the mixture stirred for another 3 hour. After aqueous work-up and silica gel chromatography (hexanes:70% ethyl acetate), the title compound was obtained.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1>C(Cl)Cl.O=[Mn]=O>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[CH:12]=[O:13])[N:3]=[CH:4][CH:5]=1
Reactant: OCc1cccc(-n2nccn2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cccc(-n2nccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (3-(2H-1,2,3-triazol-2-yl)phenyl)methanol (425 mg; 2.42 mmol) in anh. DCM (24 ml) was treated with MnO2 (3.165 g; 36.41 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 1.5 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 3-(2H-1,2,3-triazol-2-yl)benzaldehyde as a pale yellow solid. LC-MS (conditions A): tR=0.63 min.; no ionisation.
Reaction SMILES: OCC1CC1.C(Cl)(Cl)=O.Cl[C:11]([O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)=[O:12].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]([CH3:32])[CH2:27][C:28](=[O:31])[NH:29][N:30]=2)=[CH:21][CH:20]=1>CCOCC.C1(C)C=CC=CC=1>[CH:15]1([CH2:14][O:13][C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]([CH3:32])[CH2:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:21][CH:20]=2)=[O:12])[CH2:17][CH2:16]1
Reactant: O=C(Cl)OCC1CC1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: O=C(Cl)Cl
Agent: OCC1CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
3.2 g (44.4 millimoles) of (hydroxymethyl)cyclopropane, dissolved in 50 ml of absolute ether, are added dropwise to a stirred solution of 8.8 g (89.0 millimoles) of phosgene in 50 ml of absolute ether at 10°-15° C. The reaction solution is then stirred for 3 hours at room temperature. The excess phosgene is removed by means of a dry stream of nitrogen, and the ether is then removed under reduced pressure at room temperature. The cyclopropylmethyl chloroformate which remains is mixed with 6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 100 ml of absolute toluene and the mixture is kept for 7 hours at 80° C. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized twice from dimethylformamide/water. 3.0 g (34% of theory) of 6-(p-cyclopropylmethoxycarbonylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals of melting point 240°-241° C.
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([N:17]2[C:22]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][C:21]=3[O:20][C:19]([CH3:33])([CH3:32])[C:18]2=[O:34])[CH:14]=[CH:13][C:12]=1[Cl:35])(=O)C1C=CC=CC=1.CO.[OH-].[Na+].[Cl-].[NH4+]>O1CCCC1>[Cl:35][C:12]1[CH:13]=[CH:14][C:15]([N:17]2[C:22]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][C:21]=3[O:20][C:19]([CH3:33])([CH3:32])[C:18]2=[O:34])=[CH:16][C:11]=1[CH2:10][OH:9]
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(Cl)c(COC(=O)c3ccccc3)c2)C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(Cl)c(CO)c2)C1=O
Reaction time: 8 h
Yield: 61.1 %

Procedure:
To a solution of 2-chloro-5-{2,2-dimethyl-7-[(methylsulfonyl)amino]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}benzyl benzoate (compound obtained in Example 141; 80 mg) in tetrahydrofuran (3 mL)-methanol (3 mL) was added an aqueous 2N sodium hydroxide solution (0.39 mL) under ice-cooling, and the mixture was stirred at the same temperature for 8 hours. The reaction mixture was acidified with an aqueous saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=7/3→2/3) and triturated with diisopropylether/n-hexane (1/1) to give N-{4-[4-chloro-3-(hydroxymethyl)phenyl]-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (39 mg) as a colorless powder.
Reaction SMILES: C[O:2][CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15](=[O:33])[NH:16][C:17](=[O:32])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[CH:25][CH:26]=3)[N:21]([CH3:31])[CH:20]=2)=[CH:6]1)[CH3:4].Cl.CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[OH:2][CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15](=[O:33])[NH:16][C:17](=[O:32])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[CH:25][CH:26]=3)[N:21]([CH3:31])[CH:20]=2)=[CH:6]1)[CH3:4]
Reactant: COC(C)n1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(O)n1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
To a solution of 3-[l -(1-methoxy-ethyl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (3.75 gm) (from step c) above) in 100 mL of THF was added 2 N HCl (75 mL). The solution was stirred at room temperature for 3 hours, and poured into EtOAc and brine. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined EtOAc layers were dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give 1.1 gm (Yield 33%) of 3-[1-(1-hydroxy-ethyl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione.
Reaction SMILES: [N+]([O-])(O)=O.OS(O)(=O)=O.CC1(C)C2C(CC=CC=2)C(C)(C)CC1.[CH3:24][C:25]1([CH3:40])[C:34]2[C:29](=[CH:30][C:31]([N+:35]([O-])=O)=[CH:32][CH:33]=2)[C:28]([CH3:39])([CH3:38])[CH2:27][CH2:26]1>C(O)(=O)C.[Fe]>[CH3:24][C:25]1([CH3:40])[CH2:26][CH2:27][C:28]([CH3:39])([CH3:38])[C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][C:34]1=2
Reactant: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: CC1(C)CCC(C)(C)C2CC=CC=C21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A mixture of HNO3 [63%] (0.94 mL) and H2SO4 (1.5 mL) was added to 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene 5 (2.0 g, 10.6 mmol) at −10° C. and the reaction mixture was stirred for 1 h. The reaction mixture was poured into ice:water and the product was extracted with CH2Cl2. The organic layer was washed with NaOH (1N), H2O, brine, dried over MgSO4 to give after solvent evaporation 1,1,4,4-tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene (1.87 g, 76%). ref. Kagechika, H., Kawachi, E., Hashimoto, Y., Shudo, K., Himi T., J. Med. Chem., 31, 2182-2192, 1988. To a stirred solution of 1,1,4,4-tetramethyl-6-nitro-1,2,3,4-tetrahydro-naphthalene (0.593 g, 2.5 mmol) in glacial acetic acid (10 mL) was added iron powder (0.77, 13.8 mmol) over a period of 15 min. The reaction mixture was stirred at 60° C. for 3 hours. The volatiles were evaporated and the resulting oil was partitioned between EtOAc and water. Organics extracts were washed with brine, dried over MgSO4 to obtain 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine 6 (0.232 g, 46% yield) as a brown solid.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8])([O-:3])=[O:2].[Br:10]Br.O>CO>[Br:10][CH2:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: CC(=O)CCC[N+](=O)[O-]
Reactant: BrBr
Solvent: CO
Solvent: O
Product: O=C(CBr)CCC[N+](=O)[O-]
Reaction time: 2 h
Yield: 55 %

Procedure:
80.0 g (0.61 mole) of 1-nitro-pentane-4-one are dissolved in 250 ml of anhydrous methanol, whereupon 31.5 ml (0.61 mole) of bromine are quickly added under cooling with ice. The reaction mixture is stirred for a further 2 hours at a rate that the internal temperature should not exceed 40° C. To the reaction mixture 250 ml of water are added, the reaction mixture is stirred at room temperature overnight. Next morning the solution is extracted three times with 300 ml of ether each, the etheral solution is washed with a 10 % sodium carbonate solution free of acid, whereupon it is washed three times with 200 ml of water each and 200 ml of a saturated sodium chloride solution, dried over calcium chloride and evaporated. The dry residue is subjected to chromatogaphy on a silica column and eluted with a 3:1 mixture of n-hexane and ethyl acetate. Thus 70.4 g of the desired compound are obtained in the form of a faint yellow liquid, yield 55%. Rf =0.30. IR(film) :2950, 1720, 640 cm-1.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[C:25]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[NH:26][CH:27]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:10]=1[NH2:11].[C:36](Cl)(Cl)=[S:37].O>O1CCCC1.C(OCC)C>[F:8][C:9]1[CH:15]=[C:14]([CH:13]=[CH:12][C:10]=1[N:11]=[C:36]=[S:37])[O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:24]=[C:25]([CH2:28][O:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:26][CH:27]=2)=[CH:21][CH:22]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1F
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1cc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)ccc1N=C=S
Temperature: 0 °C
Yield: 78 %

Procedure:
At 23° C. and under an argon atmosphere, triethylamine (3.34 g; 0.024 mol) is added to a solution containing 2-fluoro-4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (3 g, 0.008 mol) in tetrahydrofuran (120 ml). The reaction medium is cooled down to 0° C. then the thiophosgene compound (1.01 g; 0.0088 mol) is added dropwise. Stirring is maintained at this temperature for thirty minutes then the reaction medium is returned to 23° C. and stirred at this temperature for twenty minutes. 60 ml of water and 150 ml of ethyl ether are added to the reaction medium. The two phases are separated then the organic phase is washed with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, followed by concentration to dryness then the product obtained is triturated in isopentane with traces of dichloromethane. The solid obtained is filtered then dried. A yellow-coloured powder is obtained with a yield of 78%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1cccc(C)c1O
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Product: Cc1cccc(C)c1Oc1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 70 °C
Yield: 79.8 %

Procedure:
Prepared according to Example 103 using 2,6-dimethylphenol (158 mg, 1.293 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50.0 mg, 0.168 mmol), heating at 70° C. for 17 h. Chromatographic purification (silica gel, 0-10% MeOH/DCM) furnished 2-(2-(2,6-dimethylphenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (51.4 mg, 0.134 mmol, 80% yield) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ ppm 11.08 (1H, br. s.), 8.21 (1H, d, J=8.8 Hz), 8.03 (1H, dd, J=7.6, 1.3 Hz), 7.61 (1H, dd, J=7.9, 1.3 Hz), 7.42 (1H, t, J=7.8 Hz), 7.29 (1H, s), 7.21 (3H, s), 7.10 (1H, d, J=2.2 Hz), 5.33 (1H, br. s.), 3.51 (2H, td, J=6.8, 1.2 Hz), 2.47 (2H, t, J=6.9 Hz), 2.17 (6H, s). m/z (ESI, +ve) 384.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([C:30]([F:33])([F:32])[F:31])[CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][C:23]=3[C:30]([F:31])([F:32])[F:33])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3C(F)(F)F)cccc2c1N
Yield: 81.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (116 mg, 0.375 mmol) and [4-methoxy-2-(trifluoromethyl)phenyl]boronic acid (164 mg, 0.75 mmol) were reacted to afford the title compound (124 mg, 82% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.02 (t, J=6.0 Hz, 1H), 8.45 (d, J=8.3 Hz, 1H), 7.67-7.78 (m, 2H), 7.26-7.38 (m, 3H), 3.91 (s, 3H), 3.29 (apparent q, J=7.0 Hz, 2H), 1.57 (apparent sextet, J=7.0 Hz, 2H), 0.90 (t, J=7.0 Hz, 3H). MS APCI, m/z=405 (M+H) HPLC 2.11 min.
Reaction SMILES: [CH2:1]([C@H:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].[CH2:20](I)[CH3:21].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH2:20][CH3:21])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H]1Oc2cc(C(=O)OC)ccc2N(CC)C1=O
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of (S)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine [prepared in Preparation 14(2)] (2.00 g) in dimethylformamide (20 ml) were added 60% sodium hydride (in oil) (0.37 g) and ethyl iodide (1.90 g) and the mixture was stirred under ice cooling for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give (S)-2,4-diethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.15 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([Cl:12])(=[O:11])=[O:10].Cl.Cl.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29]([C@@H:31]3[CH:36]4[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]4)[CH2:32]3)=[O:30])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1>CN(C=O)C.C(#N)C.O>[ClH:12].[CH3:8][S:9]([NH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29]([C@@H:31]3[CH:36]4[CH2:35][CH2:34][N:33]([CH2:38][CH2:37]4)[CH2:32]3)=[O:30])=[CH:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)c1
Reaction time: 18 h

Procedure:
63.6 μl (0.46 mmol) of triethylamine and 21.2 μl (0.27 mmol) of methanesulfonyl chloride are added to a solution of 60 mg (0.09 mmol) of (3R)-N-(3′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 8A) in 1 ml of DMF at room temperature. After 18 h at room temperature, the reaction mixture is diluted with a 1:1 mixture of acetonitrile and water and purified by preparative HPLC. The product fractions are concentrated, taken up in 1 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 14 mg (35.2% of theory) of the title compound are obtained.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1C=CC=CC=1)[C:14]1C=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[C:42]2[CH:49]=[N:48][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[CH3:57])[C:43]=2[N:44]=[CH:45][N:46]=1)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:20])[CH3:14]
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1C
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](C)(C)C(C)(C)C)Oc2ncnc3c2cnn3-c2cccc(Cl)c2C)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 113 %

Procedure:
A solution of 2M trimethyl aluminium in toluene (1.790 mL, 3.58 mmol) in toluene (15 mL) was added dropwise to a stirred suspension of 5-methylpyridin-2-amine (0.387 g, 3.58 mmol) in toluene (15 mL) cooled to 0° C., over a period of 2 minutes under nitrogen and the resulting suspension was stirred at 0° C. for 20 minutes. A solution of (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AE2) (1.05 g, 1.63 mmol) in toluene (10 mL) was added dropwise over 2 minutes, the mixture allowed to warm to ambient temperature and then heated to 60° C. for 20hrs. The reaction was cooled to ˜5° C. and a 10% solution of Rochelles salt (25 mL) added followed by ethyl acetate (30 mL). The organic phase was separated, washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in iso-hexane to afford the product (1.1 g, 94%). 1H NMR (400 MHz, DMSO) δ 0.89 (9H, s), 2.03 (3H, s), 2.24 (3H, s), 3.70-3.79 (4H, m), 4.03-4.07 (1H, m), 4.12-4.16 (1H, m), 5.99-6.00 (1H, m), 7.33-7.47 (8H, m), 7.55-7.62 (5H, m), 7.67-7.69 (1H, m), 7.86-7.89 (1H, m), 8.17-8.18 (1H, m), 8.50 (1H, s), 8.53 (1H, s), 10.87 (1H, s); m/z (ESI+) (M+H)+=721; HPLC tR=3.63 min.