Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:24])[C@@H:5]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]=[N:12][C:11]=2[CH:15]=1)C.O.O.[OH-].[Li+]>O1CCCC1.[Cl-].[Na+].O>[O:14]1[C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:4]([OH:24])=[O:3])=[CH:15][C:11]=2[N:12]=[CH:13]1
Reactant: CCOC(=O)[C@H](Cc1ccc2ocnc2c1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ocnc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-benzooxazol-5-yl-2-tert-butoxycarbonylamino-propionic acid ethyl ester (0.54 g, 1.61 mmol) in tetrahydrofuran (10 mL) was added water (5 mL) and lithium hydroxide monohydrate (111 mg, 2.65 mmol) and the mixture stirred at ambient temperature under argon for 1 hour. The reaction mixture was poured into water (50 mL), diluted with brine (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give crude (S)-3-benzooxazol-5-yl-2-tert-butoxycarbonylamino-propionic acid an off white solid foam which was used without further purification (0.49 g, 99%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[CH:23](OC1C=CC([N+]([O-])=O)=CC=1)=[O:24]>C(#N)C.CO.C(O)(=O)C>[CH3:1][N:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH:23]=[O:24]
Reactant: CNCc1c[nH]c2cc(C)ccc12
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(CN(C)C=O)c[nH]c2c1
Reaction time: 3 h

Procedure:
To a solution of crude methyl-(6-methyl-1H-indol-3-ylmethyl)-amine (87 mg) in acetonitrile (1 ml) was added diisopropylethyl amine (0.25 ml) and 4-nitrophenyl formate (90 mg) and stirring was continued for 3 h. The mixture was diluted with methanol and acetic acid evaporated and the residue was chromatographed on silica using n-heptane/AcOEt (1:1) to give N-methyl-N-(6-methyl-1H-indol-3-ylmethyl)-formamide as a colorless oil. MS: 202.9 ([M]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(C(=O)O)cc2)c1-c1ccc(F)cc1
Yield: 82.3 %

Procedure:
A mixture of ethyl 4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzoate (510 mg), a 2N aqueous sodium hydroxide solution (1.29 mL) and ethanol (20 mL) was stirred at 50° C. for 14 hrs. 1N Hydrochloric acid (2.6 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate, and then with saturated brine, dried (MgSO4) and concentrated. The obtained solid was recrystallized from acetone-hexane to give 4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzoic acid (390 mg, yield 82%) as colorless prism crystals. melting point: 291-292° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1.[CH2:27]([S:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:35][CH2:34]1)(=[O:32])=[O:31])[CH2:28][CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:27]([S:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([NH:46][C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:3]4[CH:4]=[C:5]([NH:8][C:9]([NH:11][CH:12]5[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]5)=[O:10])[CH:6]=[CH:7][C:2]=4[Cl:1])=[CH:19][CH:20]=3)=[O:25])=[CH:44][CH:45]=2)[CH2:35][CH2:34]1)(=[O:31])=[O:32])[CH2:28][CH3:29]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1)NC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)NC5CCCCC5)ccc4Cl)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.5 %

Procedure:
A mixture of 2′-Chloro-5′-(3-cyclohexyl-ureido)-biphenyl-4-carboxylic acid (150 mg), 4-(4-(propane-1-sulfonyl)-piperazin-1-ylmethyl)-phenylamine (236 mg) and HBTU (228 mg) in dry DMF (5 ml) containing N-methylmorpholine (0.13 ml) was stirred at room temp for 18 h. The mixture was then evaporated and the residue purified by chromatography. Gradient elution with 3%-20% 20DCM:8EtOH:1NH3 in DCM over 30 mins gave a white solid (38 mg)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1.CC(C)([O-])C.[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:24][C:25]4[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ncccc1Nc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 160 °C
Yield: 24.4 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 3-amino-2-methylpyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 21 mg, 0.19 mmol), and potassium tert-butoxide (22 mg, 0.19 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(2-methyl-pyridin-3-ylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (15 mg, 24%) as a white powder. Mass spectrum (ES) MH+=410. HRMS Calcd. for C21H28N7O2 (MH+): 410.2299. Found: 410.2299.
Reaction SMILES: [CH2:1]([O:3][C:4]#[CH:5])[CH3:2].[B]1OC2C(=CC=CC=2)O1.[F:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](I)[C:21]=1[NH2:22].[OH-].[Na+]>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>[CH2:4]([O:3][CH:1]=[CH:2][C:20]1[CH:19]=[N:18][CH:17]=[C:16]([F:15])[C:21]=1[NH2:22])[CH3:5]
Reactant: Nc1c(F)cncc1I
Reactant: C#COCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [B]1Oc2ccccc2O1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC=Cc1cncc(F)c1N
Temperature: 25 °C
Yield: 67 %

Procedure:
Ethoxyacetylene (7.9 mL, 56.4 mmol) was cooled to 0° C. and a solution of catecholborane (6.1 g, 50.8 mmol) in THF (90 mL) was added slowly. The reaction was allowed to warm to room temperature over 2 hours followed by heating to reflux for 2 hours. The reaction was cooled and 3-fluoro-5-iodo-pyridin-4-ylamine (Preparation 64, 7 g, 29.4 mmol) was added as a solution in THF (20 mL). After purging with nitrogen for 20 minutes, NaOH powder (3.52 g, 88 mmol) and Pd(PPh3)4 (1 g, 0.88 mmol) were added and the reaction heated to reflux for 20 hours. The reaction was filtered through celite, washed with EtOAc, the organic layer collected, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 50% EtOAc in hexane to afford the title compound (3.59 g)
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=2)[C:24]1=[S:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1ccc(N=C=S)cc1
Reactant: O=C(O)CNCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(N2C(=O)CN(Cc3ccccc3)C2=S)cc1
Yield: 75.4 %

Procedure:
A mixture of N-benzyl glycine (8.7 g), 4-n-butylphenyl-isothiocyanate (8.55 g), triethyl amine (5.5 g) and chloroform (150 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (2×300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. Crystallization from ethyl acetate afforded the title compound (11.4 g) as an off-white solid, m.p. 149°-151° C. Anal. Calcd. for. C20H22N2OS: C, 70.97; H, 6.55; N, 8.28. Found: C, 70.81; H, 6.76; N, 8.32. Mass spectrum (EI, M.+) m/z 338.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:35]2[CH2:40][CH2:39]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([CH:39]2[CH2:40][CH2:35]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)ccc1N
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1nc(C2CC2)ccc1N
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 3-amino-6-bromo-pyridine-2-carboxylic acid ethyl ester (prepared according to US 2006/199960; 1.0 g, 4.08 mmol), potassium phosphate (3.03 g, 14.3 mmol), tricyclohexylphosphine (0.228 g, 0.82 mmol) and water (1.25 ml) in toluene (25 ml) was added cyclopropylboronic acid (0.91 g, 10.6 mmol) and palladium (II) acetate (90 mg, 0.4 mmol). The resulting suspension was stirred at 100° C. for 24 hours. After solvent evaporation, the title compound was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as yellow solid (0.374 g, 44%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C@@H:5]([C:11]([CH3:13])=[CH2:12])[C@@H:4]1[C:14](OC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C@@H:5]([C:11]([CH3:13])=[CH2:12])[C@@H:4]1[CH2:14][OH:15]
Reactant: C=C(C)[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=C(C)[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 86157.7 %

Procedure:
To a solution of methyl (1S,2R,6R)-2-methoxy-3,3-dimethyl-6-(1-methylvinyl)cylcohexane-1-carboxylate (1.03 g) in dry diethyl ether (10 ml) at 0° C., lithium aluminum hydride (92 mg) was added in small portions. The mixture was stirred for 1 hr at room temperature. After the mixture was cooled to 0° C., the mixture was treated by successive dropwise addition of 92 ml of water, 92 ml of 15% sodium hydroxide solution and 276 ml of water. The resulting granular white precipitate was filtered, and the filtrate was concentrated to give (1R,2R,6R)-[2-methoxy-3,3-dimethyl-6-(1-methylvinyl)cyclohexyl]methanol (784 g, 91% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([S:11][C:12]3[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=3)[NH2:15])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl-].[CH3:28][C:29]1[CH:30]=[CH:31][N:32]2[C:37]=1[C:36](=[O:38])[N:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([C@@H:45]([NH3+:47])[CH3:46])=[N:33]2.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:15][C:14]1[CH:13]=[C:12]([S:11][C:10]2[C:3]3[C:2]([NH:47][C@H:45]([C:34]4[N:35]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:36](=[O:38])[C:37]5=[C:29]([CH3:28])[CH:30]=[CH:31][N:32]5[N:33]=4)[CH3:46])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccn2nc([C@H](C)[NH3+])n(-c3ccccc3)c(=O)c12
Reactant: C[Si](C)(C)CCOCn1cc(Sc2cccc(N)c2)c2c(Cl)ncnc21
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3cccc(N)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12

Procedure:
3-((4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio)aniline (100 mg, 0.25 mmol) was treated with (S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethanaminium chloride (67 mg, 0.25 mmol), cesium fluoride (15 mg, 0.10 mmol), N,N-diisopropylethylamine (400 μl, 2.3 mmol) and tert-butanol (0.78 ml) according to Preparation 163. The residue (100 mg, 80% purity) was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22].CS(C)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[S:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: Nc1ccccc1S
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(-c2nc3ccccc3s2)cc(OC)c1OC
Yield: 84.6 %

Procedure:
A solution of 3,4,5-trimethoxybenzaldehyde (19.7 g, 0.1 mol), 2-aminobenzenethiol (11.2 cm3, 0.105 mol) and dimethylsulfoxide acid (75 cm3) was heated under reflux for 24 hours. The cooled solution was added to water and extracted into ethyl acetate (3×50 cm3). The combined organic layers were dried (MgSO4), filtered and the filtrate evaporated down under reduced pressure. The solid residue was recrystallised from ethyl acetate to give 25.5 g (85.0%) of the desired product, mpt. 135° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Yield: 47.9 %

Procedure:
Stir a mixture containing 6-[1-ethyl-1-(4-hydroxy-3-methylphenyl)propyl]naphthalene-2-carboxylic acid methyl ester (0.87 g, 2.40 mmol), 1-bromopinacolone (0.64 g, 3.60 mmol), and potassium carbonate (1.0 g, 7.2 mmol) in acetone (15 mL) at RT for 16 h. Concentrate the reaction mixture and dilute the residue with EtOAc (100 mL) and water (50 mL). Adjust the pH of the mixture to 1 using 1 N HCl. Discard the aqueous layer and wash the organic layer with brine, dry over Na2SO4, then filter. Concentrate the filtrate and purify by silica gel radial chromatography (5:95 EtOAc:hex to 15:85 EtoAc:hex) to give the title compound as an off-white solid (0.53 g, 48%). MS (ES) m/e 461 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[N:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([O:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][N:14]=2)=[N:7][CH:6]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Oc1ccccc1Oc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Clc1ccc(Oc2ccccc2Oc2ncc(Cl)cn2)nc1
Yield: 76.5 %

Procedure:
With stirring, 1.80 grams (0.012 mole) of 2,5-dichloropyrimidine was added to a mixture of 2.0 grams (0.009 mole) 2-(5-chloropyridin-2-yloxy)phenol, 1.5 grams potassium carbonate, and 40 ml of methyl ethyl ketone. After the addition, the mixture was heated at reflux overnight and then poured into excess H2O. After extracting with 200 ml of ethyl ether, the extract was washed with saturated NaHCO3, H2O, brine, dried (MgSO4), filtered, and evaporated to yield a yellow solid which was recrystallized from 1-chlorobutane to give 2.3 grams of product, m.p. 108°-111°; ir (Nujol): 6.35, 6.50 (C=N), 13.20 microns; NMR (CDCl3): δ6.75 (d, 1H, pyridine ring proton), 7.35 (s, 4H, ArH), 7.65 (AB quartet, 1H, pyridine ring proton), 8.10 (d, 1H, pyridine ring proton), 8.55 (s, 2H, pyrimidine ring protons).
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]=[C:12]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[CH:10]=[C:9]([C:23](=[O:25])[CH3:24])[C:8]=1[O:26]C>CN(C)C=O>[Br:6][C:7]1[C:16]2[C:15]([CH3:17])([CH3:18])[CH2:14][CH:13]=[C:12]([C:19]([CH3:21])([CH3:20])[CH3:22])[C:11]=2[CH:10]=[C:9]([C:23](=[O:25])[CH3:24])[C:8]=1[OH:26]
Reactant: COc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CC=C2C(C)(C)C

Procedure:
As described in General Procedure L-1, sodium hydride (211 mg, 5.28 mmol) and ethanethiol (0.39 mL, 5.28 mmol) was treated with a solution of 1-(4-bromo-8-tert-butyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-104, 536 mg, 1.47 mmol) in N,N-dimethylformamide to afford the title compound after purification by flash chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[CH2:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29]>>[CH3:19][O:20][C:21]1[CH:25]=[C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)[S:23][C:22]=1[CH2:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29]
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: COc1ccsc1CCC(C)(C)O
Product: COc1cc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)sc1CCC(C)(C)O

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 4-(3-methoxy-thiophen-2-yl)-2-methyl-butan-2-ol (prepared by Pd/C hydrogenation of (E)-3-(3-Methoxy-thiophen-2-yl)-acrylic acid methyl ester, followed by reaction with MeMgBr (Step A of Method A)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH3:15])[CH2:12][N:11]([C:27](Cl)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH:37]12[CH2:43][CH:40]([NH:41][CH2:42]1)[CH2:39][O:38]2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=3)[CH3:15])[CH2:12][N:11]([C:27]([N:41]3[CH2:42][CH:37]4[CH2:43][CH:40]3[CH2:39][O:38]4)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: C1OC2CNC1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(C(=O)N2CC3CC2CO3)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a stirred solution of (3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(SR)-1-(5-trifluoromethyl-pyridin-2-yloxy)-ethyl]-pyrrolidine-1-carbonyl chloride (30 mg, 0.064 mmol) in CH2Cl2 (3 mL) were added Et3N (0.015 mL, 0.11 mmol) and 2-Oxa-5-aza-bicyclo[2.2.1]heptane (commercially available) (7 mg, 0.070 mmol). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, EtOAc) to yield 27 mg the title compound as a white solid. ES-MS m/e: 530.1 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([C:18](=[O:22])[C:19](O)=[O:20])=[C:9]1[CH2:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:26]1([CH3:35])[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:35])[CH:27]=3)=[CH:14][CH:15]=2)[C:10]2[C:18](=[O:22])[C:19](=[O:20])[O:24][CH2:23][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)c1c(CO)n(Cc2ccccc2)c2ccc(Br)cc12
Reactant: Cc1cccc(B(O)O)c1
Agent: [K]
Product: Cc1cccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)COC(=O)C2=O)c1

Procedure:
The title compound was prepared from [1-benzyl-5-bromo-2-(hydroxymethyl)-1H-indol-3-yl](oxo)acetic acid, potassium salt and m-tolylboronic acid in substantially the same manner, as described in step 4 of Example 9. The product was obtained as a grey solid, mp: 225–226° C.; Mass spectrum (ESI, [M+H]+) m/z 382. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.22 (d, 1H, J=8.40 Hz), 7.65 (dd, 1H, J=8.45 and 1.83 Hz), 7.49 (s, 1H), 7.47–7.34 (m, 3H), 7.31 (d, 1H, J=7.33 Hz), 7.27 (d, 2H, J=8.40 Hz), 7.18 (d, 1H, J=7.48 Hz), 5.92 (s, 2H), 5.55 (s, 2H), and 2.39 ppm (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]([F:21])([F:20])[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2.Br[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:25]([Cl:38])[CH:24]=1>C1(C)C=CC=CC=1>[Cl:38][C:25]1[CH:24]=[C:23]([N:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([F:8])([F:20])[F:21])[CH:11]=3)[CH2:16]2)[CH:28]=[C:27]([CH3:29])[C:26]=1[NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)cc(Cl)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc(Cl)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (154 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-methyphenyl)-3,3-dimethylbutanamide (200 mg, 0.63 mmol) were then added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[N:7][C:6]=1Cl)=[O:4].[NH3:14]>C(O)C>[CH3:1][N:2]([CH3:13])[C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[N:7][C:6]=1[NH2:14])=[O:4]
Reactant: N
Reactant: CN(C)C(=O)c1cc(Cl)nnc1Cl
Solvent: CCO
Product: CN(C)C(=O)c1cc(Cl)nnc1N
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To 3,6-dichloro-pyridazine-4-carboxylic acid dimethylamide (100 mg, 0.456 mmol) was added saturated ammonia in absolute ethanol (2 mL) and the mixture irradiated in a microwave reactor to 180° C. for 45 min. 1 mL of saturated ammonia in ethanol was added and irradiation continued for an additional 30 min. The sample was concentrated in vacuo, washed with saturated ammonium chloride (1×) and brine (1×). Saturated sodium bicarbonate was added to the aqueous layer and was extracted with ethyl acetate (3×). The combined organics were dried over sodium sulfate to afford 3-amino-6-chloro-pyridazine-4-carboxylic acid dimethylamide (54.9 mg, 60%). MS: m/z 389 (M+H+).