Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:19])[N:5]([C:12]([CH:16]([CH3:18])[CH3:17])([CH3:15])[C:13]#[N:14])[C:6]2=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>CC(C)=O>[CH2:28]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:19])[N:5]([C:12]([CH:16]([CH3:17])[CH3:18])([CH3:15])[C:13]#[N:14])[C:6]2=[O:11])[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: CC(C)C(C)(C#N)N1C(=O)c2cccc(O)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2c1C(=O)N(C(C)(C#N)C(C)C)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-hydroxy-α-isopropyl-α-methyl-1,3-dioxo-2-isoindolineacetonitrile (25.5 g, 0.099 mol), potassium carbonate (75.0 g, 0.543 mol) and acetone is stirred for 4 hours at reflux temperature under a nitrogen atmosphere, cooled to room temperature and treated with allyl bromide (34.1 mL, 0.395 mol). The reaction mixture is stirred overnight at reflux temperature, cooled to room temperature and filtered. The filtrate is concentrated in vacuo, diluted with ether, washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title product as a yellow-orange semi-solid, 26.9 g (91.5% crude yield). The sample is purified by flash chromatography (silica gel, CH2Cl2) to afford a colorless solid, mp 54°-58° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C(C)=O)cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 82 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:17]=2)=[N:8][N:9]([CH3:15])[C:10]=1[O:11][CH:12]([F:14])[F:13]>O1CCCC1>[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23]([NH:4][CH:1]3[CH2:3][CH2:2]3)(=[O:24])=[O:25])[CH:17]=2)=[N:8][N:9]([CH3:15])[C:10]=1[O:11][CH:12]([F:14])[F:13]
Reactant: NC1CC1
Reactant: Cn1nc(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)c(Cl)c1OC(F)F
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(Cl)c(S(=O)(=O)NC3CC3)c2)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.9 g (16 mmol) of cyclopropylamine was added to a solution of 3 g (7.6 mmol) of 4-chloro-3-(4-chloro-3-chlorosulfonylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 25 ml of tetrahydrofuran. The mixture was stirred at room temperature for 4 hours and then concentrated to dryness. The solid residue was washed with a little diisopropyl ether. Yield: 3 g.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:10]=1[NH2:11].[Br:17][CH2:18][C:19](Br)=[O:20]>C(Cl)Cl>[Br:17][CH2:18][C:19]([NH:11][C:10]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=1[CH3:8])=[O:20]
Reactant: O=C(Br)CBr
Reactant: Cc1ccc(N)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)CBr)c(C)c1

Procedure:
117 g of triethylamine and 140 g of 2,4-dimethylaniline are dissolved in 2 l of methylene chloride, and a solution of 233 g of alpha-bromoacetyl bromide in 400 ml of methylene chloride is added with ice-cooling, at at most 15° C., within 30 min. After a reaction time of 30 min, the precipitate is filtered off with suction, the residue is dissolved in 3 l of methylene chloride and combined with the filtrate and washed twice with 2 l of water and 2 l of sat. sodium chloride solution. The mixture is dried over sodium sulphate, filtered off with suction and concentrated, and the residue is recrystallized from ethanol. This gives 193 g of the title compound.
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.Cl[C:23]1[N:28]=[C:27]([C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[O:30])[C:26]([CH3:42])=[CH:25][C:24]=1[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=1.[NH2:53][C:54]1[N:59]=[CH:58][C:57](B(O)O)=[CH:56][N:55]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[NH2:53][C:54]1[N:59]=[CH:58][C:57]([C:23]2[N:28]=[C:27]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:33][CH2:32]3)=[O:30])[C:26]([CH3:42])=[CH:25][C:24]=2[C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=2)=[CH:56][N:55]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cnc(N)nc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 2-aminopyrimidin-5-yl-boronic acid, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and sodium carbonate in dioxane/water at 80° C. to give the title compound as dark brown oil. MS: 511.4 (MH+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[C@@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[N+]=[N-].[H][H]>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[C@@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1
Reactant: [H][H]
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](OCCN=[N+]=[N-])[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2c(F)cccc2[C@H](OCCN)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Reaction time: 8 h
Yield: 107.5 %

Procedure:
To a solution of (R)-tert-butyl 2-((S)-(2-azidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (423 mg, 0.9 mmol) in EtOAc (20 mL) was added wetted Pd/C (42 mg) and the mixture was hydrogenated overnight using a balloon of hydrogen. The mixture was filtered through a pad of Celite and the solvent was removed to give (R)-tert-butyl 2-((S)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (430 mg, 100%). MS (E/Z): 445 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.Cl[CH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][C:23]1=[O:31].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(CC(=O)C)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:19][CH2:20][CH2:21][N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: COc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COc1ccc2c(C3CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)noc2c1
Yield: 37.8 %

Procedure:
A mixture of 4.1 g of 6-methoxy-3-(4-piperidyl)-1,2-benzisoxazole, 3.7 g of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 3.1 g of sodium carbonate, a few crystals of potassium iodide and 125 ml of 2-methyl-4-pentanone was stirred and heated under reflux under nitrogen for 16 hrs. The reaction was poured into 300 ml of water, the layers were separated and the aqueous layer was extracted twice with dichloromethane. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield an oil. The oil was triturated with ether and the solid was collected. The solid was recrystallized twice from toluene to yield 2.7 g (37.7%) of product, mp 176°-178°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(Cc2ccccc2)c1
Yield: 95.6 %

Procedure:
3-benzoyl-benzoic acid methyl ester (653 mg, 2.72 mmol) was stirred in trifluoroacetic acid (3 mL) with triethylsilane (1.3 mL, 8.15 mmol) at room temperature for 22 h. The reaction mixture was diluted with ethyl acetate and washed with an aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated. The resultant oil was subjected to column chromatography (25 hexanes: 1 ethyl acetate) to provide 3-benzyl-benzoic acid methyl ester (589 mg, 2.6 mmol) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]3[N:26]([CH:27]=2)[CH:25]=[CH:24][S:23]3)=[CH:16][C:15]=1[O:28][CH3:29].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>O.CO>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[CH:25]=[CH:24][S:23]4)=[CH:16][C:15]=2[O:28][CH3:29])=[CH:33][CH:32]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1cc(-c2cn3ccsc3n2)ccc1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2cn3ccsc3n2)ccc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Potassium carbonate (106 g) was added to 490 ml of an anhydrous DMF suspension of 120 g of the compound obtained in Step 1. After stirring for 2 hours, to the mixture was added 82.9 g of p-chlorobenzyl bromide at 0° C., and stirred for 3 hours at 0° C. and for 42 hours at room temperature. The reaction mixture was mixed with 500 ml of methanol and 450 ml of water, and stirred at 70° C. for 30 minutes. After cooling the mixture to room temperature, the precipitated crystals were suction filtered, rinsed with 50% methanol and water, and dried under reduced pressure, thereby yielding 102 g of transparent crystals of the desired compound (“Example Compound 23”).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([NH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NCC(=O)c1ccccc1
Product: CC(=O)NCC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
About 200 grams of 2-aminoacetophenone were added to about 350 ml. of acetic anhydride at 0° C. After warming to ambient temperature, the reaction mixture was stirred 4 hours and, upon addition of ice water, a precipitate formed which was filtered and washed with water. The precipitate was suspended in ether and washed separately with 1 l. each of 1 N sodium hydroxide, water, 1 N hydrochloric acid, and again with 1 N sodium hydroxide. The ether suspension was dried with sodium sulfate, filtered, and concentrated. Ligroin was added and the desired product was collected by filtration. The identity of the final product was confirmed by NMR analysis; yield 215 grams, m.p. 69° C.
Reaction SMILES: F[B-](F)(F)F.[C:6]([C:9]1[CH:10]=[C:11]([N+:23]([O-:25])=[O:24])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([N+]#N)[CH:14]=1)([OH:8])=[O:7].C(OC(=O)C)(=[O:28])C>C(O)(=O)C>[OH:28][C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([N+:23]([O-:25])=[O:24])[C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: N#[N+]c1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: O=C(O)c1cc(O)c(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
5-Carboxy-3-nitro-2phenylbenzenediazonium tetrafluoroborate (110 g ) is added in portions to a stirred and refluxing mixture of acetic anhydride (275 ml) and acetic acid (275 ml). The mixture is refluxed for a further 4-5 hours and is then poured into ice-water (about 4 liters). The mixture is left for 20 hours, and the precipitated crude 3-acetoxy-5-nitro-4-phenylbenzoic acid is collected by filtration, washed with water and dried. It is saponified by heating with 4 N sodium hydroxide (250 ml) for 30 minutes; the resulting solution is left at 5° C for about 20 hours and is then filtered. The filtrate is acidified with 4 N hydrochloric acid to precipitate 3-hydroxy-5-nitro-4-phenylbenzoic acid. It is collected by filtration, washed with water and dried. After recrystallization from aqueous methanol, the acid is obtained with a melting point of 213°-215° C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[N:11]2[CH:12]=[CH:13][C:14]([C:17]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])([CH3:19])[CH3:18])=[C:15]([F:16])[C:10]2=[N:9][CH:8]=1.C([Sn](Cl)(CCCC)CCCC)CCC.[Cl:42][C:43]1[N:48]=[C:47](Cl)[CH:46]=[CH:45][N:44]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O>[Cl:42][C:43]1[N:48]=[C:47]([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:17]([O:20][Si:21]([CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:24][CH3:25])([CH3:18])[CH3:19])=[C:15]([F:16])[C:10]3=[N:9][CH:8]=2)[CH:46]=[CH:45][N:44]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2c1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Isopropylmagnesium chloride (2.0M in THF; 5.7 ml, 11.4 mmol) was added dropwise to a stirred, cold (−78° C.) solution of 3-bromo-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine (4.0 g, 10.3 mmol) in THF (80 ml). After 10 min, tri-n-butyltin chloride (3.22 ml, 11.9 mmol) was added in a single portion and the mixture was stirred for 30 min, then warmed to ambient temperature. 2,4-Dichloropyrimidine (2.31 g, 15.5 mmol) was added and the mixture degassed by bubbling through N2. Tetrakis(triphenylphosphine)palladium(0) (1.19 g, 1.03 mmol) and copper(I) iodide (19.7 mg, 0.1 mmol) were then added in single portions and the reaction was heated to reflux for 18 h. On cooling, water (80 ml) was added and the phases separated. The aqueous was extracted with EtOAc (40 ml) and the combined organics washed with brine (40 ml), dried over MgSO4, filtered and concentrated in vacuo. Purified by column chromatography (silica, 0 to 5% MeOH in CH2Cl2) and the semi-pure product washed with 1:2 Et2O/isohexane to afford 3-(2-chloropyrimidin-4-yl)-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine as a white amorphous solid (3.4 g): m/z (ES+) 421 (100%, [MH]+) and 423 (30).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[N:31]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][C:16](=[O:19])[CH:15]=[C:14]3[NH:20][C:21]2[C:22]([Cl:28])=[CH:23][N:24]=[CH:25][C:26]=2[Cl:27])[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: C1CNCCNC1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN1CCCNCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 1,4-diazepane following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 8 h). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 2H), 7.85 (d, 1H), 7.00 (d, 1H), 4.69 (s, 1H), 3.95 (t, 2H), 3.88 (s, 3H), 2.79 (t, 2H), 2.74 (m, 2H), 2.60-2.52 (m, 4H), 2.40 (t, 2H), 1.74 (m, 2H), 1.63 (m, 2H), 1.39 (m, 4H), 1.30 (m, 2H) [NH's not seen]; MS (ESI): 534.3.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:13]([C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[CH:12][N:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)NN=Cc1c[nH]c(Cc2ccccc2)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ncc2cnc(Cc3ccccc3)n12

Procedure:
A 7.0 gm. portion of 3-[(2-benzyl-4-imidazolyl)methylene]carbazic acid ethyl ester in 50 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product as white crystals, m.p. 215°-217° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)=[N:2]1.IC.[C:15](=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCCCC>CN(C=O)C>[CH3:15][N:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cnc(-c2cc[nH]n2)s1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CCCCCC
Product: Cn1ccc(-c2ncc(C=O)s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
2-(1H-pyrazol-3-yl)thiazole-5-carbaldehyde (0.25 g, 1.3 mmol) was dissolved in DMF (5 mL) and iodomethane (0.26 mL, 4.1 mmol) and potassium carbonate (0.6 g, 4.1 mmol) were added. The reaction was stirred for 3 h at room temperature until the reaction was deemed complete by TLC (80% EtOAc\hexane). The reaction was poured into ice water (50 mL), and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under vacuum to afford 2-(1-methyl-1H-pyrazol-3-yl)thiazole-5-carbaldehyde as a yellow solid (0.1 g, 38% yield). 1H-NMR (DMSO-d6): δ 10.0 (s, 1H) 8.60 (s, 1H). 8.50 (s, 1H), 8.05 (s, 1H), 3.89 (s, 3H); LC-MS m/z calcd for [M+H]+, 194.03. found, 194.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.[Pd](Cl)Cl.O1CCCC1>[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Brc1ccc2sccc2c1
Reactant: C#CCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC#Cc1ccc2sccc2c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 5-bromobenzothiophene (50.0 g), 1-decyne (35.7 g), triethylamine (71.2 g) and dry tetrahydrofuran (150 ml), under nitrogen, was added bis(triphenylphosphine)palladium (II) chloride (1.65 g) followed by copper (I) iodide (0.233 g) with stirring, at room temperature. The reaction mixture was covered with foil and stirred at reflux, under nitrogen, over the weekend. Additional bis-triphenylphosphine)palladium (II) chloride (0.5%) and 0.25% copper (I) iodide were added, and the reaction mixture was stirred at reflux for three days, cooled, filtered through a bed of celite and the filter cake was washed with ether. The residue was flash chromatographed (silica, 1% ethyl acetate-heptane). The appropriate fractions were collected and evaporated to give 56.3 g (89%) of product.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1csc(C(C)C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1nc(CO)cs1
Temperature: -78 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
A solution containing the product from Example 56B (18 g, 90.5mmol) in dichloromethane (100 mL) was treated with diisobutyl aluminum hydride (150 mL, 1 M in dichloromethane) dropwise at −78° C. over 2 hours and the mixture was stirred at −78° C. for 2 hours. Acetic acid (10 mL) was added at −78° C. and the mixture was warmed to 25° C. A 10% solution of aqueous sodium potassium tartrate was added and the mixture was stirred vigorously for 1 hour. The reaction was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-5% ethyl acetate/dichloromethane to give the title compound (3.84 g, 27% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[CH:50][C:43]=23)[CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH:48]1[C:44]2=[N:45][CH:46]=[N:47][C:42]([NH:41][C@H:37]3[CH2:38][CH2:39][CH2:40][N:35]([C:11](=[O:13])[CH2:10][NH:9][C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:36]3)=[C:43]2[CH:50]=[N:49]1
Reactant: c1nc(N[C@H]2CCCNC2)c2cn[nH]c2n1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCC[C@H](Nc2ncnc3[nH]ncc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a cooled solution of 2-(3,5-dichlorophenylamino)acetic acid (102 mg, 0.45 mmol) at 0° C. in anhydrous DMF (5 mL), HOBt (135 mg, 0.68 mmol) was added and the reaction mixture was stirred for 10 min before EDCI (132 mg 0.68 mmol), (S)—N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.45 mmol) and DIEA (117 mg, 0.90 mmol) were added in succession. The reaction mixture was allowed to warm to rt and stirred overnight. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with EtOAc (50 mL) and was washed with water (3×20 mL). The EtOAc layer was then dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled intermediate (62 mg, 32%). 1H NMR (400 MHz, CDCl3): δ 11.42 (bs, 1H), 8.58 and 8.49 (2s, 1H), 7.98 (s, 1H), 6.71 and 6.68 (2s, 2H), 6.41 and 6.39 (2s, 2H), 5.29-5.18 (m, 1H), 4.40-4.09 (m, 2H), 3.94-3.42 (m, 3H), 3.18-3.03 (m, 1H), 2.27-2.20 (m, 1H), 1.97-1.56 (m, 4H). LC-MS: m/z [M+1]=420.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.S(OC)(O[CH3:34])(=O)=O>C(O)C>[CH3:34][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COS(=O)(=O)OC
Solvent: CCO
Product: CNc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
A solution of [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone (100 mg) and dimethyl sulfate (150 mg) in ethanol was stirred at r.t. for 4 hrs. The solution was concentrated and purified by semi-HPLC to give [4-(3-methylamino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone as a gum.