Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[N:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:8][N:9]([C:14]3[N:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)cc2)C1

Procedure:
The title compound (D122) (180 mg) was prepared according to the experimental procedure described in Description 121 starting from 3-(4-fluorophenoxy)azetidine) (D49) (177.89 mg, 1.064 mmol) and 2-chloro-5-(trifluoromethyl)nicotinic acid (200 mg, 0.886 mmol)
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(C3=NC(C)(C)CO3)cnc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)COC(c2cnc3cc(O)ccc3c2)=N1

Procedure:
A solution of 7-methoxy-3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)quinoline (2.56 g, 10 mmol) prepared in stage A and BBr3 (7.41 g, 30 mmol) in dichloromethane (40 mL) are stirred for 12 hours at room temperature. The mixture was quenched with saturated sodium hydrogen carbonate. Extraction with dichloromethane, drying (MgSO4) and evaporation furnished the desired compound.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1Br.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1[NH:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20]
Reactant: CC1(C)CC(n2ncc(Br)c(Br)c2=O)CC(C)(C)C1
Reactant: CN(C)CCN
Product: CN(C)CCNc1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1Br

Procedure:
4-Bromo-5-(2-dimethylaminoethyl)amino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one was prepared from 4,5-Dibromo-2-(3,3,5,5-tetramethyl cyclohexyl)pyridazin-3-one in a similar manner using 2-Dimethylaminoethyl amine (4 equivalents). 1H NMR (300 MHz CDCl3) 7.51 (s, 1H), 5.53 (m, 1H), 5.33 (m, 1H), 3.34 (m, 2H), 2.60 (m, 2H), 2.3 (s, 6H), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:22])([CH3:21])[CH2:12][O:13][Si](C(C)(C)C)(C)C)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[C:32]2[C:28](/[C:29](=[CH:35]/[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=3[F:43])/[C:30](=[O:34])[NH:31]2)=[CH:27][CH:26]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:21])([CH3:22])[CH2:12][OH:13])[C:29]2([C:28]3[C:32](=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=3)[NH:31][C:30]2=[O:34])[CH:35]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[F:43])=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1F
Reactant: CC(C)(C/C=N/CC(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(CO)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid-tert-butyl ester (3.1 g, 9.0 mmol) prepared in Example 100 and E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one (2.5 g, 8.1 mmol) prepared in Example 2 in dichloromethane (100 mL) were added triethylamine (7.5 mL, 54 mmol) and AgF (1.9 g, 15 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (15 mL), and DBU (16 g, 65 mmol) was added. The reaction mixture was heated at 120° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (10-80% EtOAc in hexanes) to give as rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a light yellow solid (1.0 g, 23%)
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.[NH2:12][C:13]1[S:14][C:15]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[S:14][C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[O:9])=[CH:5][N:4]=1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Reactant: O=C(O)c1ccc(CCl)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(CCl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
6-(Chloromethyl)nicotinic acid (172 mg, 1.00 mmol) obtained in Step 1, 2-amino-4-(2-furyl)-5-morpholinothiazole (251 mg, 1.00 mmol) obtained in Step 1 of Example 29 and PyBOP (572 mg, 1.10 mmol) were dissolved in DMF (4 mL), and triethylamine (0.307 mL, 2.20 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under the reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:3) to afford the entitled Compound 36 (194 mg, 48%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11]C(=O)C)[CH2:4][CH2:3]1.Cl.[OH-].[Na+].[Cl-].[Na+]>O>[O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH2:11])[CH2:4][CH2:3]1
Reactant: CC(=O)NC1CCC(=O)c2sccc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: NC1CCC(=O)c2sccc21

Procedure:
A mixture of N-(4,5,6,7-tetrahydro-7-oxobenzo[b]-thien-4-yl)acetamide (16.0 g), water (100 ml) and concentrated hydrochloric acid (100 ml) is stirred and heated at reflux for an overnight period. The mixture is cooled, made alkaline with 50% aqueous sodium hydroxide, and sautrated with sodium chloride. The mixture is then extracted with methylene chloride (3×250 ml). The extracts are combined, dried over magnesium sulfate and then evaporated to dryness in vacuo to afford the title compound as a yellow-brown syrup.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[O:1][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]2)[N:17]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3cccs3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a cold (0° C.) solution of tert-butyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (8 g, 32.7 mmol) in anhydrous DCM (150 mL) was added thiophene-2-carbonyl chloride (4.8 g, 32.7 mmol) followed by DIEA (7.2 mL, 39.2 mmol). The reaction mixture was stirred at RT for 12 hours and then filtered. The filtrate was evaporated and the residue was refluxed in pyridine (100 mL) for 3 hours. The solvent was removed under vacuum and the residue was dissolved in DCM. The organic layer was washed with a 10% aq. solution of sodium bicarbonate, water, brine and dried. The solvent was concentrated and the residue was purified by chromatography (Pet. Ether/EtOAc 7/3) to give 2.2 g (20%) of The title compound as a solid. TLC—Pet ether/EtOAc (9/1): Rf=0.75. HPLC purity>97%.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([N:7]1[C:11]2=[N:12][C:13]([CH2:25][CH3:26])=[C:14]([CH2:23]O)[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:10]2[CH:9]=[N:8]1)[CH3:6].[N-:27]=[N+:28]=[N-:29].[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CS(C)=O.CO>[N:27]([CH2:23][C:14]1[C:13]([CH2:25][CH3:26])=[N:12][C:11]2[N:7]([CH2:5][CH3:6])[N:8]=[CH:9][C:10]=2[C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN=[N+]=[N-]
Temperature: 85 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (SOCl2, 50.37 ml, 82.11 g, 69 mmol) was added dropwise over 15 minutes to a suspension of [1,6-d]ethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (13.98 g, 46 mmol, e.g. which can optionally be as described in Intermediate 5) in toluene (140 ml) at room temperature. The mixture was then heated at reflux at about 85° C. for 4 hours, was allowed to cool, and then was evaporated to dryness and azeotroped with three further portions of toluene. The residue obtained was dissolved in dry dimethylsulfoxide (100 ml) and treated with sodium azide (4.49 g, 69 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was poured into saturated aqueous sodium bicarbonate solution and was extracted with 3 portions of ethyl acetate. The combined organic extracts were washed with saturated brine and water, and were then dried (Na2SO4), the drying agent was filtered off, and the filtrate was evaporated to dryness. The residue obtained was purified by flash chromatography, eluting with 1:1 cyclohexane:ethyl acetate. Fractions containing the product without substantial amounts of impurities were evaporated to give the title compound (5.6 g+4.75 g=10.35 g).
Reaction SMILES: [C:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[C:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CCCCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: C1=C(c2cccc3c2OCCNC3)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A mixture of tert-butyl 9-(cyclohexa-1-en-1-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (170 mg, 0.516 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (112 mg, 81.8%) as a solid.
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[Cl-].[NH4+].I[CH:14]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]([C:30]2[CH:35]=[CH:34][C:33]([O:36]C(=O)C(C)(C)C)=[CH:32][CH:31]=2)[C:21]2[C:16](=[CH:17][C:18]([O:43][CH3:44])=[CH:19][CH:20]=2)[CH2:15]1>>[OH:36][C:33]1[CH:32]=[CH:31][C:30]([C:22]2[C:21]3[C:16](=[CH:17][C:18]([O:43][CH3:44])=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:23]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc2c(c1)CC(I)C(c1ccccc1)C2c1ccc(OC(=O)C(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Potassium tert-butoxide solution 0.5 mol/L in dimethyl sulfoxide (1.10 mL, 0.55 mmol) was added to and dissolved in 2-iodo-7-methoxy-3-phenyl-4-(4-pivaloyloxyphenyl)-1,2,3,4-tetrahydronaphthalene (5′, 74.4 mg, 0.138 mmol) under an argon atmosphere, and the resulting aubergine solution was stirred for 1 hour while heating at 90° C. Thereafter, the reaction mixture was cooled with ice, and then a saturated aqueous ammonium chloride solution (7 mL) was added thereto and sufficiently stirred, followed by extracting four times with a mixed liquid (4 mL) of hexane/diethyl ether (1:1). An organic layer was collected, followed by drying with anhydrous magnesium sulfate and concentration thereof. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain the title compound (7, 41.1 mg, yield 89%), the same as that of Example 4.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:1][Si:2]([O:13][C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=1)([CH3:4])[CH3:3]
Reactant: Oc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C[Si](C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (11 ml, 87 mmol) was added dropwise to a stirred solution of 4-bromophenol (10.0 g, 58 mmol) in toluene (25 ml) and pyridine (20 ml) at 0° C. The stirred mixture was heated to ambient temperature during 3 hours. The reaction mixture was filtered and the organic solution evaporated to yield pure 4-bromophenyl trimethylsilyl ether. The silyl ether can be further purified by distillation (b.p. 122° C., 20 mmHg). Yield after distillation: 13.70 g (75%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:17][NH2:18])=[CH:11][C:10]=1[C:30]([CH3:33])([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:17][NH:18][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:11][C:10]=1[C:30]([CH3:33])([CH3:32])[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1cc(CC(CN)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(CC(CNS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 3-(4-benzyloxy-3-tert-butylphenyl)-2-benzyloxycarbonylaminopropylamine (1.27 g, 2.84 mmol) in methylene chloride (29 ml), TEA (0.6 ml, 4.26 mmol) and then methanesulfonyl chloride.(0.3 ml, 3.69 mmol) were added slowly under cooling with ice. After stirring for 30 min., the mixture was mixed with water and extracted with chloroform. The organic layer was dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:ethyl acetate:n-hexane=1:1:2), giving the titled compound (1.23 g, 83%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[S:42]([NH:45][C:46]1[C:47]([O:61][CH3:62])=[N:48][CH:49]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:51]=1)(=[O:44])=[O:43].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[CH3:33][C@H:28]1[O:29][C@@H:30]([CH3:32])[CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:50]4[CH:51]=[C:46]([NH:45][S:42]([C:36]5[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:35]=5[F:34])(=[O:44])=[O:43])[C:47]([O:61][CH3:62])=[N:48][CH:49]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[N:24][CH:23]=2)[CH2:27]1
Reactant: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
To a solution of 6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (0.2 g, 0.411 mmol) and 2,4-difluoro-N-[2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.228 mg, 0.534 mmol) in 1,4-dioxane (2 ml) was added chloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.5 mg, 0.021 mmol), potassium phosphate tribasic (0.262 g, 1.23 mmol) and water (0.2 ml). The reaction mixture was heated to 120° C. with stirring for 3 h under microwave irradiation, then filtered through a silica SPE, eluting with methanol. The solvent was removed and the residue partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous extracted with further dichloromethane (2×2.5 ml). The combined organics were concentrated under a stream of nitrogen and the residue dissolved in DMSO and a few drops of dichloromethane (3 ml) and purified by MDAP (method H) in 3 injections. The appropriate fractions were evaporated in vacuo to give the title compound as a pale brown solid (0.105 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:32][CH2:33][CH3:34])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:31]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:47].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:47][C:9]1[C:8]2[N:31]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:32][CH2:33][CH3:34])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]3)=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCCn1c(COCC)nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCn1c(COCC)nc2c(N)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Reaction time: 0.5 h

Procedure:
To a stirring solution of tert-butyl 4-{[2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate (5.17 g, 10.5 mmol) in chloroform (100 mL) was added 3-chloroperoxybenzoic acid (3.62 g, 10.5 mmol, based on 50% purity). After 30 minutes, concentrated ammonium hydroxide (50 mL) was added and the mixture was stirred for 30 minutes. p-Toluenesulfonyl chloride (2.00 g, 10.5 mmol) was added in 3 portions and the mixture was stirred for 16 hours. The layers were separated and the organic fraction was sequentially washed with 5% aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Recrystallization from acetonitrile afforded 2.58 g of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as a reddish-tan crystalline solid, mp 194-195° C.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:7][C@H:6]1[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[CH:2]=[CH2:3].[CH2:33](Br)[C:34]1C=CC=[CH:36][CH:35]=1.C(Br)C=C>>[CH2:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH2:7][C@H:6]1[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1)[C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:3]=1
Reactant: C=CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Solvent: C=CCBr
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CN(C2CCOCC2)C[C@H]1OCc1ccccc1

Procedure:
The title compound was synthesized in similar fashion to rel-N-(2-{[(3R,4R)-4-(allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide, benzyl bromide was substituted for allyl bromide and was isolated as a white solid. 1H-NMR (MeOD) δ: 1.51 (m, 2H), 1.82 (m, 2H), 2.40 (m, 1H), 2.58 (m, 1H), 2.76 (m, 1H), 3.02-3.14 (m, 2H), 3.40 (m, 2H), 3.91-3.98 (m, 3H), 4.05 (s, 2H), 4.41 (m, 1H), 4.60 (m, 2H), 7.26-7.38 (m, 5H), 7.70 (t, J=7.7 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 8.15 (d, J=7.7 Hz, 1H), 8.23 (s, 1H) MS m/z: 506 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:22]=[CH:21][C:9]2[O:10][CH2:11][CH2:12][N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:8]=2[CH:7]=1)(=O)C.[OH-].[Na+]>O1CCOCC1.O>[OH:4][CH2:5][C:6]1[N:22]=[CH:21][C:9]2[O:10][CH2:11][CH2:12][N:13]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:8]=2[CH:7]=1
Reactant: CC(=O)OCc1cc2c(cn1)OCCN2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOc2cnc(CO)cc21
Yield: 108.5 %

Procedure:
A solution of 1,1-dimethylethyl 7-[(acetyloxy)methyl]-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (0.84 g, 2.7 mmol) in 1,4-dioxane (20 ml) and water (5 ml) was treated with 2M sodium hydroxide solution (2.72 ml, 5.4 mmol). After 0.5 hour the mixture was concentrated to a volume of 5 ml and then partitioned between ethyl acetate and water. The organic extract was dried and evaporated to afford a colourless oil (0.78 g, 105%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][N:33]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:32](=[O:36])[CH:31]=2)=[CH:28][CH:29]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(Cl)cc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 28.8 %

Procedure:
The compound was prepared from tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (250 mg, 0.685 mmol) and 4-(4-chlorophenyl)pyridine-2(1H)-one (100 mg, 0.418 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (59 mg, 18%) as a solid, that contained an impurity: ESI MS m/z 490 [M+H]+.