Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2cccc(Br)c2)cn1
Yield: 12 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 3-bromophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (14 mg, 12%) which was obtained as an off-white solid. MS: m/e=399.4 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.[C:26](O)(=[O:28])C>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:26]=[O:28])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: C1N2CN3CN1CN(C2)C3
Product: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Yield: 60 %

Procedure:
It has now been found that reaction of 2,4-di-tert-butylphenol with hexamethylenetetramine in glacial acetic acid followed by quenching with water or aqueous acid, extraction with a water insoluble non-polar solvent and filtration through silica gel provides 3,5-di-tert-butylsalicylaldehyde in more than 60% yield and of a purity suitable for the production of chiral Mn-Salen catalysts. Alternatively, reaction of 2,4-di-tert-butylphenol with HMT in glacial acetic acid followed by quenching with an aqueous acid, separating the aqueous phase from the organic phase and recrystallizing the organic phase in methanol provides 3,5-di-tert-butylsalicylaldehyde in more than 40% isolated yield and a purity suitable (>95%) for the production of the catalyst.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH3:18][CH:17]([C:14]1[CH:15]=[CH:16][C:8]([O:7][CH2:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:8]=2)=[C:9]([CH:13]=1)[C:10]([O:12][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:11])[CH3:19]
Reactant: CC(C)c1ccc(O)c(C(=O)O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
K2CO3 (3.83 g, 27.7 mmol) was added to a stirred solution of 2-hydroxy-5-(1-methylethyl)benzoic acid (may be prepared as described in Description 1; 2.0 g, 11.10 mmol) in acetone (80 ml), followed by the addition of (bromomethyl)benzene (4.75 g, 27.7 mmol). The mixture was refluxed for 12 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to a yellow solid. Flash chromatography over silica gel, using 1:10 ethyl acetate-petroleum ether yielded the title compound as a yellow oil. 1.0 g.
Reaction SMILES: C(C[CH2:4][NH:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#N.[CH3:33][N:34]([CH3:44])[S:35]([N:38]1[CH2:43]CN[CH2:40][CH2:39]1)(=[O:37])=[O:36]>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:10])([CH3:9])[CH3:11])[C:6]([N:5]3[CH2:4][CH2:43][N:38]([S:35](=[O:37])(=[O:36])[N:34]([CH3:44])[CH3:33])[CH2:39][CH2:40]3)=[O:32])=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Product: CN(C)S(=O)(=O)N1CCN(C(=O)[C@@H](NC(=O)n2nc(-c3ccc(F)c(F)c3)c3c2CCOC3)C(C)(C)C)CC1

Procedure:
Compound 112 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with N,N-dimethylpiperazine-1-sulfonamide. LCMS (+ESI) m/z=569.4 [M+H]+. 1H NMR (CDCl3) δ 7.92 (d, J=9.6 Hz, 1H), 7.48-7.52 (m, 1H), 7.28-7.32 (m, 1H), 7.19-7.26 (m, 1H), 4.81-4.84 (m, 3H), 3.91-3.98 (m, 3H), 3.81-3.86 (m, 1H), 3.65-3.71 (m, 1H), 3.53-3.60 (m, 1H), 3.29-3.47 (m, 2H), 3.16-3.26 (m, 4H), 2.85 (s, 6H), 1.12 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[O:32])=[CH:26][CH:25]=1)C1C=CC=CC=1.CO>O1CCCC1.[C].[Pd]>[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[O:32])=[CH:28][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1N
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.2 %

Procedure:
After dissolving (4-{4-[3-(4-fluorophenyl)ureido]phenoxy}-7-methoxyquinolin-6-yl)carbamic acid benzyl ester (100 mg) in a mixture of tetrahydrofuran (10 ml)-methanol (10 ml), 10% palladium carbon (10 mg) was added and the mixture was stirred for 7 hours at room temperature under hydrogen gas at 1 atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated to obtain the title compound (60 mg) as a solid.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[I-].C[S+](C)(C)=O.[CH3:13][C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH2:24])[N:17]=2.[NH4+].[Cl-]>CS(C)=O.C1COCC1.C(OCC)(=O)C>[CH3:13][C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:1][CH2:24]1)[N:17]=2
Reactant: CC(C)(C)[O-]
Reactant: C=C(c1ccccc1)c1ccc2nc(C)sc2n1
Agent: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Potassium 2-methylpropan-2-olate (32.3 g, 288 mmol) was almost completely dissolved in 250 mL DMSO under argon in a 1 L 3-necked RBF. Trimethyl sulfoxonium iodide (63.3 g, 288 mmol) was added in 2 portions, separated by 15 min. The reaction mixture became wamm after the addition. After 15 min, the reaction was fitted with a water-cooled reflux condenser and heated to 60° C., and a solution of 2-methyl-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine (41.5 g, 164 mmol) in 125 mL THF was added slowly dropwise via addition funnel over 30 min. The resulting dark red reaction mixture was cooled briefly and then poured onto ice and 300 mL sat'd aq. NH4Cl was added. Ethyl acetate (500 mL) was added and the layers were separated. The aq. Layer was extracted with ethyl acetate and the combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography, 330 g, 0-40% EAlhexanes gave 2-methyl-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as an orange solid. MS (ESI) m/z: calculated: 266.1; Observed: 267.1 (M++1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:45])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33](OC3C=CC([N+]([O-])=O)=CC=3)=[O:34])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:47]1[C:51]2([CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:24]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]([N:54]3[CH2:55][CH2:56][C:51]4([CH2:50][CH2:49][CH2:48][CH2:47]4)[CH2:52][CH2:53]3)=[O:34])=[O:45])[CH2:21][CH2:22]2)=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reactant: C1CCC2(C1)CCNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCCCCCCOC(=O)N1CCC2(CCCC2)CC1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Yield: 93 %

Procedure:
A solution of the carbonate (2.0 g, 3.2 mmol) produced in Example 5, 8-aza-spiro [4,5]-decane hydrochloride (680 mg, 3.9 mmol) and triethylamine (2.7 ml, 19 mmol) in 30 ml of anhydrous dimethylformamide was stirred under nitrogen at room temperature for 5 hours. The reaction was diluted with methylene chloride, extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4), and the solvent removed under reduced pressure to give 1.85 g of a white solid. Recrystallization of this solid from methylene chloride-diisopropyl ether gave 1.0 g (50%) of the title compound as a white crystalline solid, mp 83-85° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[NH:18]1)([O:14][CH2:15][CH3:16])=[O:13].[OH-].[K+]>C(O)C>[C:12]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)n1[nH]c(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)n1c2ccccc2c(=O)n1Cc1ccc([N+](=O)[O-])cc1
Yield: 59 %

Procedure:
4-Nitrobenzyl bromide (540 mg) was added to a mixture of 1,2-dihydro-1-carboethoxy-3H-indazol-3-one (206 mg) and potassium hydroxide (67 mg) in ethanol (10 ml). The mixture was heated under reflux for 30 minutes. The cooled solution was clarified by filtration and the filtrate was evaporated. The residue was purified by column chromatography using methylene chloride as eluant to give 1,2-dihydro-1-carboethoxy-2-(4-nitrobenzyl)-3H-indazol-3-one (Ex. 39) as a solid, m.p. 123-124° C. in 59% yield.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[NH2:23][CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[N+:20]([C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:18]=[CH:19][C:2]=1[NH:30][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([C:24]#[N:23])=[CH:26][CH:27]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Reactant: N#Cc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 100.4 %

Procedure:
To a mixture of 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (2.0 g, 6.7 mmol) and 4-(aminomethyl)benzonitrile (1.1 g, 8.3 mmol) in DMA (20 mL) was added DIPEA (3.5 mL, 20 mmol) and heated to 100° C. for 16 h. The mixture was cooled and poured into water (400 mL). The resulting solids were collected by filtration to provide 2.76 g of the title compound. The material was used without further purification. MS (ESI): mass calcd. for C24H18N4O3, 410.43; m/z found 411.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][C:12]1[C:20]2[NH:19][C:18](=[O:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][C:12]1[C:20]2[N:19]([CH3:32])[C:18](=[O:21])[N:17]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCOc1cccc2c1[nH]c(=O)n2Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCOc1cccc2c1n(C)c(=O)n2Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of [2-(1-benzyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (0.100 g, 0.252 mmol) in 2 mL of anhydrous N,N-dimethylformamide was added sodium hydride (11 mg of a 60% dispersion in mineral oil) under nitrogen. The suspension was stirred at room temperature for ten minutes and then methyl iodide (0.018 mL, 0.277 mmol) was added in one portion. Stirring was continued for one hour and the reaction mixture was added to 150 mL water, and extracted twice with 75 mL ethyl acetate. The combined organic fraction was washed with 100 mL brine, dried over sodium sulfated and concentrated in vacuo. The residue was purified by flash chromatography (18% to 28% ethyl acetate in hexane) to afford 92 mg (0.223 mmol, 88.5%) of [2-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester as a clear oil. MS: 412 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=3)=[CH:11][CH:10]=2)O1.Br[C:27]1[N:32]2[N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=[C:31]2[CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:21]([C:18]1[N:19]=[CH:20][C:15]([CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:32]4[N:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=[C:31]4[CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:23]=2)=[CH:16][CH:17]=1)#[N:22]
Reactant: O=C(Nc1nc2cccc(Br)n2n1)C1CC1
Reactant: CC1(C)OB(c2ccc(OCc3ccc(C#N)nc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Temperature: 90 °C

Procedure:
5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-pyridine-2-carbonitrile (10 g, 0.03 mol, 1.1 equiv.) was added to a solution of cyclopropanecarboxylic acid(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (7.6 g, 0.027 mol) in 1,4-dioxane/water (4:1; 70 mL). K2CO3 (7.45, 0.054 mol, 2 eq.) and PdCl2dppf (5%) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 4 to 16 h under N2 until completion (monitored by LCMS). 1,4-Dioxane was removed under vacuum, and water/EtOAc were added and the solid was filtered. The obtained solid was dissolved in methanol/DCM, dried over MgSO4 and the final compound was obtained after purification by flash chromatography, eluted with neat EtOAc
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([O:14][CH3:15])=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[S:16](=[O:21])(=[O:20])[N:17]([CH3:19])[CH3:18])=[CH:7][CH:6]=1)=O.[BH4-].[Li+]>C1COCC1>[CH3:19][N:17]([CH3:18])[S:16]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([CH2:3][OH:2])[C:13]=2[O:14][CH3:15])[CH:9]=[N:10]1)(=[O:20])=[O:21]
Reactant: COC(=O)c1ccc2cnn(S(=O)(=O)N(C)C)c2c1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(CO)ccc2cnn(S(=O)(=O)N(C)C)c12
Reaction time: 68 h
Yield: 98.3 %

Procedure:
To a solution of 1-dimethylsulfamoyl-7-methoxy-1H-indazole-6-carboxylic acid methyl ester (6.23 g, 19.9 mmol) in anhydrous THF (100 mL) at 0° C. under an atmosphere of nitrogen was added lithium borohydride solution (2 M in THF, 39.8 mL, 79.5 mmol) and the mixture was allowed to reach RT with stirring. After 68 h, the mixture was quenched with saturated aqueous ammonium chloride solution (40 mL) and water (80 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound as an oil (5.58 g, 98%). LCMS (Method G): RT=2.73 min, [M+H]+=286.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[S:12][C:13]([CH2:16]Cl)=[CH:14][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].[CH2:18]([C:21]1[NH:22][C:23]2[C:24]([N:31]=1)=[N:25][C:26]([CH3:30])=[CH:27][C:28]=2[CH3:29])[CH2:19][CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[S:12][C:13]([CH2:16][N:31]3[C:24]4=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]4[N:22]=[C:21]3[CH2:18][CH2:19][CH3:20])=[CH:14][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCCc1nc2nc(C)cc(C)c2[nH]1
Reactant: CCOC(=O)C1(c2ccc(CCl)s2)CC=CC1
Product: CCCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)OCC)CC=CC2)s1

Procedure:
Alkylation was performed on (5) as described in Example 1, Step 5, above, using 2-propyl-5,7-dimethylimidazo[4,5-b]pyridine (10) to yield the title compound (9).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:16]([F:19])([F:18])[F:17])([C:5]1[CH:6]=[CH:7][C:8]2[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:15]=1)[OH:4].[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH:22]1([C:25]([N:14]2[C:8]3[CH:7]=[CH:6][C:5]([C:3]([C:2]([F:1])([F:20])[F:21])([C:16]([F:19])([F:17])[F:18])[OH:4])=[CH:15][C:9]=3[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:26])[CH2:24][CH2:23]1
Reactant: O=C(Cl)C1CC1
Reactant: OC(c1ccc2c(c1)CCCCN2)(C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(C1CC1)N1CCCCc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21

Procedure:
To 200 ml dry toluene is added 6.3 g (0.020 mole) α,α-bis(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-7-methanol and 3.0 g (0.025 mole) cyclopropane carboxylic acid chloride. The solution is stirred and heated at reflux under nitrogen for sixteen hours, then cooled and evaporated at reduced pressure. The residual solid is recrystallized from chlorobutane to give 5.0 g, m.p. 165°-167°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:12]C(=O)OC(C)(C)C)[CH2:6]2)#[N:2].[ClH:20]>O1CCOCC1.CCOCC>[ClH:20].[NH2:12][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C#N)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#Cc1ccc2c(c1)CC(N)C2
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl (5-cyano-2,3-dihydro-1H-inden-2-yl)carbamate (1.85 g, 7.18 mmol) in dioxane (30 mL) at room temperature was added HCl in dioxane (18 mL of a 4.0 M solution; 72 mmol). The mixture was stirred for ca. 18 hr and diluted with ether. Solids were collected by filtration and rinsed thoroughly with ether, affording the title compound as a tan solid. 1H NMR (400 MHz, methanol-d4) δ ppm 7.65 (s, 1H), 7.59 (d, 1H, J=7.9 Hz), 7.46 (d, 1H, J=7.9 Hz), 4.14 (m, 1H), 3.51-3.43 (m, 2H), 3.10-3.04 (m, 1H).
Reaction SMILES: C(=O)=O.S(=O)(=O)(O)O.[C:9]([CH2:13][OH:14])([F:12])([F:11])[F:10].C[O:16][CH:17](O)[C:18]([F:21])([F:20])[F:19]>>[C:9]([CH:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[OH:14])([F:12])([F:11])[F:10]
Reactant: COC(O)C(F)(F)F
Reactant: OCC(F)(F)F
Agent: O=C=O
Agent: O=S(=O)(O)O
Product: OC(OCC(F)(F)F)C(F)(F)F
Temperature: 75 °C

Procedure:
A 250 mL round bottom flask was equipped with a thermometer, magnetic stir bar, addition funnel and dry ice condenser leading to a receiver cooled with an isopropanol cold bath held at about −30° C. by the addition of portions of dry ice as needed. Sulfuric acid (175 g) was placed in the 250 mL flask and CF3CH2OH (Aldrich, 57.8 g, 0.578 mole) placed in the receiver. Trifluoroacetaldehyde methyl hemiacetal (Alfa Aesar, 50 g, 90% purity, 0.346 mole) was placed in the addition funnel and added rapidly dropwise to the sulfuric acid solution which was heated to 75° C. as the addition proceeded. The aldehyde began to distill from the sulfuric acid solution at a pot temperature of about 64° C. After the completion of the addition the sulfuric acid solution was held at 75° C. for an additional hour. The receiver had gained 26.3 g in weight and this solution was used without purification in the next step.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[C:36](B(O)O)([CH3:38])=[CH2:37]>>[C:36]([C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:34])([F:33])[F:35])[CH:3]=1)([CH3:38])=[CH2:37]
Reactant: C=C(C)B(O)O
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Br)cc4C(F)(F)F)c3)S2)CC1
Product: C=C(C)c1ccc(Cn2ncc3cc(C=C4SC(N5CCN(C)CC5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
5-[1-(4-Isopropenyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one and isopropenylboronic acid following General Procedure F.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:7]([O:24][CH3:25])[CH:6]=1)(=O)C>Cl>[ClH:11].[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:7]([O:24][CH3:25])[CH:6]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)CCCCN1CCCCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)CCCCN1CCCCC1
Reaction time: 0.5 h

Procedure:
1-(4-Acetylamino-5-chloro-2-methoxyphenyl)-5-(piperidin-1-yl)pentan-1-one was dissolved in 2N hydrochloric acid (25 mL) and the solution was stirred for 30 minutes. The solution was cooled in an ice bath to form a precipitate. The precipitate was collected by filtration and washed with water. Drying in a vacuum oven at 70° C. gave 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(piperidin-1-yl)pentan-1-one hydrochloride (0.65 g, 2 mmol), m.p. 220°-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH3:13])[C:5]#[N:6].[Br:14]Br>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:14])[C:9]=1[NH:10][CH2:11][CH2:12][CH3:13])[C:5]#[N:6]
Reactant: BrBr
Reactant: CCCNc1ccc(C#N)cc1Cl
Solvent: CO
Product: CCCNc1c(Cl)cc(C#N)cc1Br
Reaction time: 0.5 h

Procedure:
Step AR2. To 3-chloro-4-(propylamino)benzonitrile (365 mg, 1.87 mmol) in MeOH (10 ml) was added bromine (300 mg, 1.87 mmol) in MeOH (2 mL) dropwise. After stirred for 30 minutes, the solvent was removed and crude 3-chloro-5-bromo-4-(propylamino)-benzonitrile was obtained (549 mg, 100%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[C:12]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:7][O:8][CH2:9][CH2:10][N:11]1[C:12]([CH3:22])=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:15]1[C:1](=[O:5])[C:2]([Cl:4])=[O:3]
Reactant: COCCn1cc(-c2ccccc2)cc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: COCCn1c(C)cc(-c2ccccc2)c1C(=O)C(=O)Cl

Procedure:
Oxalyl chloride (0.19 g, 1.53 mmol) was added to a solution of 1-(2-methoxy-ethyl)-2-methyl-4-phenyl-1H-pyrrole (0.30 g, 1.39 mmol) in chloroform (5 mL) at 0° C. and slowly warmed the ambient temperature to RT over 30 min. Completion of reaction and removal of excess oxalyl chloride in vacuo afforded the intermediate acid chloride, [1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-oxo-acetyl chloride which was taken in chloroform (5 mL). This was then added to a solution of 3-fluoro-4-morpholin-4-yl-phenylamine (0.19 g, 0.97 mmol) in chloroform (5 mL) with triethyl amine (0.28 g, 2.78 mmol). The reaction was stirred for 30 min at ambient temperature and then diluted with water and extracted into chloroform. Combined organic extracts were washed with saturated bicarbonate solution, dried over anhydrous sodium sulfate and stirred over neutral alumina for 10 min. The mixture was filtered and concentrated in vacuo to afford N-(3-fluoro-4-morpholin-4-yl-phenyl)-2-[1-(2-methoxy-ethyl)-5-methyl-3-phenyl-1H-pyrrol-2-yl]-2-oxo-acetamide (0.26 g, 40%) as pale yellow solid.