Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[CH:20]=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[CH:20]([OH:21])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2C=O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2C(O)c2ccccc2)C1
Reaction time: 15 h
Yield: 79 %

Procedure:
To a solution of 3-(5-bromo-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.70 mmol) in CH2Cl2 (10 mL) was added a solution of PhMgBr (1M in THF, 1 mL). The reaction was allowed to stir for 15 h then quenched with 1N HCl (4 mL). After 10 min, the mixture was made basic with 1N NaOH (10 mL), and extracted with CH2Cl2 (3×20 mL). The organic layers were combined and dried. Chromatography of the resulting residue (SiO2; EtOAc/Hexanes) gave the title compound (0.24 g, 79%). MS (ESI): mass calcd. for C21H24BrNO4, 433.1; m/z found, 434.4 [M+H]+. 1H NMR (CDCl3): 7.41-7.23 (m, 6H), 7.17 (dd, J=8.2, 1.7, 1H), 6.61 (d, J=1.7, 1H), 6.04 (s, 1H), 4.90-4.68 (m, 1H), 4.32-4.01 (m, 2H), 3.95-3.68 (m, 2H), 2.04-2.10, 1H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][C:9](=[O:12])[CH2:10][Cl:11])=[CH:5][CH:4]=1.[ClH:15].Cl.[CH2:17]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:11].[ClH:15].[CH2:17]([N:26]1[CH2:31][CH2:30][N:29]([CH2:10][C:9]([NH:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:12])[CH2:28][CH2:27]1)[C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19]
Reactant: COc1ccc(CNC(=O)CCl)cc1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)CN2CCN(CC(=O)c3ccccc3)CC2)cc1

Procedure:
A mixture of N-(4-methoxybenzyl)-2-chloroacetamide (3.65 mmol), N-phenacyl piperazine dihydrochloride (3.97 mmol) and K2CO3 (10.5 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-30)(61%), M+ 381.
Reaction SMILES: [CH2:1]([S:3]([Cl:6])(=[O:5])=[O:4])[CH3:2].Cl.Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH:30]4[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]4)[CH2:26]3)=[O:24])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>CN(C=O)C>[ClH:6].[CH2:1]([S:3]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([C@@H:25]3[CH:30]4[CH2:29][CH2:28][N:27]([CH2:32][CH2:31]4)[CH2:26]3)=[O:24])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
39.1 mg (0.30 mmol) of ethanesulfonyl chloride and 84.8 μl (0.61 mmol) of tiethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated, mixed with 2 ml of a 1:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 26 mg (35.2% of theory) of the title compound are obtained. HPLC (Method 1): Rt=3.71 min. MS (ESIpos): m/z=414 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4](Br)[CH:3]=1.C([Li])CCC.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl>C(OCC)C>[CH3:15][Si:16]([CH3:19])([CH3:18])[C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Si:16]([CH3:19])([CH3:18])[CH3:15])[CH:5]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(Br)cc([Si](C)(C)C)c1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 141.4 %

Procedure:
1,3,5-Tribromobenzene (125 g, 0.4 mol), was dissolved in anhydrous diethylether (1 L), and cooled to -70° C. n-Butyllithium (250 mL, 1.6 M in hexanes, 0.4 mol) was added dropwise over a one-hour period keeping the temperature near -70° C. The solution was stirred for an additional 20 minutes at -70° C. and then warmed to -10° C. over a two-hour period. The solution was then recooled to -70° C. and trimethylchlorosilane (45 g, 0.4 mol) was added over a one hour period. The solution was allowed to stir and warm to room temperature overnight. The solution was cooled to -70° C. and an additional 0.4 mol n-butyl lithium was added over a one-hour period. The resulting slurry was stirred for one hour at -70° C., warmed to -10° C. over a two-hour period and then recooled to -70° C. An additional 0.4 mol of trimethylchlorosilane was added and the slurry was allowed to warm to room temperature overnight. The mixture was quenched with water and the layers were separated. The organic layer was washed twice with sodium bicarbonate solution and with salt brine then dried over magnesium sulfate. The solvents were evaporated under vacuum and the product distilled twice under vacuum to yield 85.2 g (70%) of a colorless liquid. b.p. 100-105° C. @ 0.5 mmHg.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][C:4]#[N:5].[CH3:7][N:8]([CH:10](OC)OC)[CH3:9]>>[CH3:9][N:8](/[CH:10]=[C:3](/[C:2](=[O:1])[CH3:6])\[C:4]#[N:5])[CH3:7]
Reactant: CC(=O)CC#N
Reactant: COC(OC)N(C)C
Product: CC(=O)/C(C#N)=C/N(C)C

Procedure:
3-Oxo-butyronitrile (113 g, 1.36 mol) and DMF-DMA (215 g, 1.81 mol) were heated to 80° C. for two hours. The solvents were then removed under vacuum to yield a solid. The solid was partitioned between ethyl acetate (1.5 L) and saturated sodium bicarbonate solution (1 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (1.5 L). The organic layers were combined and the solvent removed under vacuum to yield the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[C:8]=2[N+:12]([O-])=O)[N:3]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[C:8]=2[NH2:12])[N:3]=1
Reactant: Cc1ccc2c([N+](=O)[O-])c(C)ccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(N)c(C)ccc2n1
Yield: 73.3 %

Procedure:
To a solution of 2,6-dimethyl-5-nitro-quinoline (192 mg, 0.95 mmol) in ethanol (9.3 mL) and water (4.7 mL) were added iron powder (280 mg, 5.0 mmol) and NH4Cl 280 mg, 5.2 mmol). The mixture was heated at reflux for 2 h, then cooled filtered. The filtrate was concentrated under reduced pressure, and the aqueous residue was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash column (hexane/ethyl acetate gradient) gave 2,6-dimethyl-quinolin-5-ylamine (120 mg, 73%).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[C:25](Cl)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH2:1][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: CC(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 39.2 %

Procedure:
To a solution of 4-methylcarbonyloxy-4'-hydroxybiphenyl (2.3 g) and triethylamine (1.1 g) in methylene chloride (50 ml) was gradually added dropwise undecanoyl chloride (n-C10H21COCl) (2.1 g). Dimethylaminopyridine (0.3 g) was further added thereto and the mixture was stirred for 24 hours. After the solvent was distilled off, the residue was added to tetrahydrofuran containing tert-butylamine and the mixture was refluxed at 70° C. for 2 hours and hydrolyzed. After the solvent was distilled off, dilute hydrochloric acid was added to the residue to render the solution neutral and the solution was extracted with diethyl ether. After the solvent was distilled off, the residue was washed with hexane and recrystallized from water/ethanol (1/9) solution to obtain the titled compound (about 1.4 g).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23](=O)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC([N:30]([C:38]2C=CC=[CH:40][CH:39]=2)[C:31]2[CH:36]=[CH:35][C:34](C)=[CH:33][CH:32]=2)=CC=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:34]5[CH:35]=[CH:36][C:31]6[N:30]([C:6]7[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=7)[C:38]7[C:39]([C:32]=6[CH:33]=5)=[CH:40][CH:7]=[CH:8][CH:9]=7)([C:34]5[CH:33]=[CH:32][C:31]6[N:30]([C:11]7[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=7)[C:38]7[C:18]([C:36]=6[CH:35]=5)=[CH:17][CH:22]=[CH:40][CH:39]=7)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Reactant: Cc1ccc(N(c2ccccc2)c2ccc(C)cc2)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: c1ccc(-c2c3c(nc4ccccc24)-c2ccccc2C3(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Yield: 188.7 %

Procedure:
Referring to the reaction formula above, 10-phenyl-11H-indeno[1,2-b]quinolin-11-one (860 mg, 2.80 mmol) and 4-methyl-N-phenyl-N-(p-tolyl)aniline (1668 mg, 6.10 mmol) are placed in a round bottom flask and then dissolved in 5 ml of dichloromethane. Subsequently, 800 μl of Eaton's reagent is slowly dripped into the flask to promote reaction. After 12 hours of reaction at 100° C., the crude product is extracted with 20 ml of dichloromethane and sodium bicarbonate for three times. Finally, an organic layer of the crude product is dehydrated with magnesium sulfate and concentrated to be sublimated and purified to obtain 2050 mg of 10-phenyl-11,11-bis(9-phenyl-9H-carbazol-3-yl)-11H-indeno[1,2-b]quinoline. The percentage yield is 87.6%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:30][C:29]3[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:32][CH:31]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(C=O)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(CNc2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 14 h

Procedure:
To a solution of [3-(4-formyl-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (30 mg, 0.1 mmol) and 4-methanesulfonylaniline (30 mg, 0.17 mmol) in 1,2-dichloroethane (1 mL) was added sodium trisacetoxy borohydride (50 mg, 0.23 mmol). The reaction mixture was stirred for 14 h and then loaded directly on a silica gel column. Elution with 33% hexane in ethyl acetate provided (3-{4-[(4-methanesulfonyl-phenylamino)-methyl]-phenyl}-isoxazol-4-yl)-carbamic acid tert-butyl ester as a waxy solid. This was dissolved in 4M HCl in dioxane and stirred for 1 h. Removal of volatiles under reduced pressure afforded 3-{4-[(4-methanesulfonyl-phenylamino)-methyl]-phenyl}-isoxazol-4-ylamine hydrochloride as a white solid. MH+=344.3
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=1.[NH2:16][C:17]1[N:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[CH:19][N:18]=1>>[NH2:16][C:17]1[N:22]=[C:21]([C:23]([NH:13][CH2:12][C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:14])[F:15])=[CH:7][CH:8]=2)=[O:24])[CH:20]=[CH:19][N:18]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: NCc1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: Nc1nccc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)n1
Yield: 22 %

Procedure:
The title compound is prepared in 22% yield (42 mg, a white solid) from (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (140 mg, 0.58 mmol) and 2-aminopyrimidine-4-carboxylic acid (80 mg, 0.58 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: C(=[N:8][C:9]([CH2:19][CH3:20])([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])C1C=CC=CC=1.Cl>>[CH2:13]([O:12][C:10](=[O:11])[C:9]([NH2:8])([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:14]
Reactant: CCCCC(CC)(N=Cc1ccccc1)C(=O)OCC
Agent: Cl
Product: CCCCC(N)(CC)C(=O)OCC
Temperature: 10 °C
Yield: 70 %

Procedure:
A solution of the product from step (c) (1 mole) in 1N aqu. HCl (1.2 moles) was stirred for 10 minutes at room temperature, then washed with toluene. The pH of the remaining aqueous phase was adjusted to 7 using 12.5% w/v sodium hydroxide, then cooled to 10° C., further basified to pH 12 and extracted with toluene. The extracts were combined, washed with brine, dried and evaporated in vacuo. The residue was distilled to give the desired product as an oil (70-80% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](Br)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].C1(P(C2C=CC=CC=2)[C:44]2[CH:53]=[CH:52][C:51]3[C:46](=CC=CC=3)[C:45]=2[C:54]2C3C(=CC=CC=3)C=[CH:56][C:55]=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-].C1(CCC[Zn+])C=CC=CC=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([CH2:56][CH2:55][CH2:54][C:45]3[CH:46]=[CH:51][CH:52]=[CH:53][CH:44]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1Br
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCc1ccccc1
Temperature: 100 °C

Procedure:
To a mixture of Example 5D (200 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (28.9 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (22 mg) in tetrahydrofuran (3 mL) was added (3-phenylpropyl)zinc(II) bromide (1.42 mL). The resulting suspension was heated in a Biotage microwave synthesizer at 100° C. for 30 minutes. The reaction mixture was filtered through a sintered glass funnel. The filtrate was concentrated, and the residue was purified by preparative TLC, eluting with 40% acetone in petroleum ether, to provide the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=O>C(#N)C.CCOC(C)=O>[CH2:7]([N:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:15]=[CH:27][S:24]1(=[O:26])=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Nc1ccccc1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=S1(=O)C=Cc2ccccc2N1Cc1ccccc1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
Cesium carbonate (18.0 g, 55 mmol) and benzyl bromide (6.6 mL, 55 mmol) were added to a solution of N-(2-formylphenyl)methanesulfonamide (5.50 g, 27.6 mmol) in acetonitrile (120 mL). The reaction mixture was heated at 60° C. for 16 h and then cooled to ambient temperature. The mixture was diluted with EtOAc (200 mL) and filtered. The filtration cake was washed with EtOAc (200 mL) and the combined organics were concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:5) to afford 1-benzyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (6.5 g, 87% yield) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:28]=[CH:29][N:30]=3)[N:15]=[C:16]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:28]=[CH:29][N:30]=3)[N:15]=[C:16]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(-c2cc(Nc3ccc(OC)c(OC)n3)c3nccn3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)nc1OC
Yield: 77.5 %

Procedure:
To a stirred solution of methyl 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (0.135 g, 0.333 mmol) in dioxane (20 mL) and H2O (10 mL) was added NaOH (133 mg, 3.33 mmol) at 25° C. After 2 h the mixture was washed with ether (10 mL) and the aqueous layer was adjusted to pH=4 with concentrated HCl, then it was concentrated and filtered. The solid was washed with ether and dried to afford 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.101 g, 77%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.98 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 8.11-8.03 (m, 4 h), 7.69 (s, 1H), 7.43 (d, 1H, J=8.4 Hz), 7.13 (d, 1H, J=8.7 Hz), 4.04 (s, 3H), 3.79 (s, 3H). LC-MS: [M+H]+, 391.9, tR=1.454 min, HPLC: 98.08% at 214 nm, 95.71% at 254 nm, tR=3.628 min.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13](O)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].Cl.[NH2:23][CH2:24][C:25]1[C:26](=[O:34])[NH:27][C:28]([CH3:33])=[C:29]([F:32])[C:30]=1[CH3:31].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[F:32][C:29]1[C:30]([CH3:31])=[C:25]([CH2:24][NH:23][C:13]([C:12]2[C:7]3[CH:6]=[N:5][N:4]([CH:2]([CH3:3])[CH3:1])[C:8]=3[N:9]=[C:10]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:11]=2)=[O:14])[C:26](=[O:34])[NH:27][C:28]=1[CH3:33]
Reactant: Cc1[nH]c(=O)c(CN)c(C)c1F
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1[nH]c(=O)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(C)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (169 mg, 0.60 mmol), 3-(aminomethyl)-5-fluoro-4,6-dimethyl-2(1H)-pyridinone hydrochloride (136 mg, 0.660 mmol), EDC (150 mg, 0.780 mmol), HOAT (106 mg, 0.780 mmol), and N-methylmorpholine (0.264 mL, 2.400 mmol) in DMF (3 mL) was stirred at room temperature for 3 days. water (15 mL) was added to the slurry, and it was stirred for an hour. The precipitate was then collected by vacuum filtration and rinsed with EtOH (4 mL), and the solid was dried in the vacuum oven overnight to give the title compound as 220 mg (76%). LCMS E-S (M+H)=435.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, 7H), 2.18 (d, J=2.78 Hz, 3H), 2.25 (d, J=2.02 Hz, 3H), 4.45 (d, J=4.80 Hz, 2H), 5.37 (spt, J=6.65 Hz, 1H), 8.19-8.25 (m, 2H), 8.29 (s, 1H), 8.44 (s, 1H), 8.74-8.81 (m, 2H), 9.07 (t, J=4.80 Hz, 1H), 11.66 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11].Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2,6-Dichlorophenyl)acetic acid (2.55 g) was dissolved in anhydrous MeOH (60 mL) and HCl (gas) was passed through the mixture and the resulting solution was stirred at room temperature for 18 h. The solvent was then evaporated to give (2,6-dichlorophenyl)acetic acid methyl ester (2.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.[CH2:13]([N:15](CC)[CH2:16]C)C.Cl.CNC>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:15]([CH3:16])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)N(C)C
Temperature: 60 °C

Procedure:
To a solution of α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 120 mL of tetrahydrofuran was added 12 mL (88.0 mmol) of triethylamine and 5.4 g (66.0 mmol) of dimethylamine hydrochloride. The reaction mixture was heated at 60° C. in a sealed tube for three hours, cooled to ambient temperature and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography using a methanol/chloroform gradient as eluent and concentrated to dryness to yield 1.86 g (44%) of the desired isomer as a yellow oil. MS (ion spray) 193.9 (M+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[Br-].[Li+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C@H:20]2[CH2:33]OS(C)(=O)=O)=[CH:15][C:14]=1[F:39]>COCCOC.CN(C=O)C.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:21][C@H:20]2[CH2:33][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[O:3])=[CH:15][C:14]=1[F:39]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Reactant: Oc1ccccn1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2ccccc2=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
60% Sodium hydride (45.3 mg, 1.13 mmol) was added to a mixed solution of 2-hydroxypyridine (86 mg, 0.91 mmol) in 1,2-dimethoxyethane (2 ml) and DMF (1 mL) at room temperature. After stirring at room temperature for 5 min, lithium bromide (131 mg, 1.51 mmol) was added at room temperature. After stirring for 10 min, to the reaction mixture was added a solution of tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (331 mg, 0.76 mmol) in 1,2-dimethoxyethane (2 mL). The reaction mixture was stirred at 80° C. overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (267 mg, 0.611 mmol, 81%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[C:27]([N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:26])[CH:3]=2)[C:31]1=[O:35])(=[O:29])[CH3:28]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)c(F)c2)C1=O
Yield: 33.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (418 mg) described in Preparation Example 121 and 1-acetylimidazolidin-2-one (128 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (156 mg) was obtained.