Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C1[C@H](C2C=CC=C([N+]([O-])=O)C=2)C(C(O)=O)=C(C)NC=1C)=O.[C:25]1([CH:31]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:32][CH2:33][N:34]2[CH2:38][CH2:37][C:36]([CH3:40])([OH:39])[CH2:35]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>C(O)(C)C>[C:41]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:32][CH2:33][N:34]2[CH2:38][CH2:37][C@:36]([CH3:40])([OH:39])[CH2:35]2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC1(O)CCN(CCC(c2ccccc2)c2ccccc2)C1
Agent: COC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: C[C@]1(O)CCN(CCC(c2ccccc2)c2ccccc2)C1
Temperature: 30 °C
Yield: 18.6 %

Procedure:
According to Example 15, (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid and 1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-ol were synthesized. To a solution of D-bis(paramethylbenzoyl)tartaric acid ((+)-Di-1,4-toluoyl-D-tartaric acid) (280 g, 0.7 mol) in isopropanol (300 mL) was added a solution of 1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-ol (280 g, 0.95 mol) in isopropanol (300 mL) at 90° C. After the solution became clear, the solution was cooled down to 30° C. slowly, and filtered to produce a white solid, which was treated with sodium hydroxide to produce (S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-ol (52 g) in a yield of 18.6%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([O:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:6]1([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([O:22][CH2:23][C:24]4[CH:25]=[C:26]([C:27]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:28])[CH:30]=[CH:31][CH:32]=4)[CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C1CCNC1
Reactant: O=C(O)c1cccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)c1
Product: O=C(c1cccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)c1)N1CCCC1

Procedure:
Example 96 (E96) was prepared from pyrrolidine and 3-(3-cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acid (E95) using the procedure outlined for Example 90 (E90); MS (ES+), m/e 419 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:27]#[N:28].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(C#N)cc1Br
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C#N)cc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Temperature: 90 °C
Yield: 65.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.20 g, Example 33), 3-bromo-4-methoxybenzonitrile (0.20 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) in toluene (5 ml) and ethanol (2 ml), with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.17 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:38]1[C:46]2[C:41](=[C:42](B3OC(C)(C)C(C)(C)O3)[C:43]([F:47])=[CH:44][CH:45]=2)[CH:40]=[CH:39]1)(C(C)(C)C)(C)C>>[F:47][C:43]1[C:42]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:41]2[C:46](=[CH:45][CH:44]=1)[NH:38][CH:39]=[CH:40]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(C(N)=O)N1CCN(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(4-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (123 mg) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 114 mg of 121 following reverse phase HPLC purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=O)[CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:6])[CH3:2].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:3]([CH2:4][CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:6])[CH2:17][CH3:18])[CH3:2]
Reactant: CCN(CC)C(=O)C(C)Nc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CC(C)Nc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
2.31 g of N,N-diethyl 2-(3,4-dichloroanilino)propionamide were dissolved in 15 ml of dry tetrahydrofuran. This solution was added dropwise in 5 minutes to a stirred suspension of 0.61 g of lithium-aluminium-hydride in 25 ml of dry tetrahydrofuran. The reaction mixture was refluxed for 6 hours and was left to stand overnight. The next day 0.6 ml of water, 1.5 ml of 15% sodium hydroxide solution and 1.5 ml of water were added successively. After filtration the organic layer was washed with water, dried and filtered. After evaporating the solvent, 2.06 g of the desired product were obtained; identification by means of thin-layer chromatography. The product was purified by means of columnchromatography (acetone as an eluent), after which 1.41 g of an organge oil was obtained; nD25 =1.5404.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10]([CH3:22])[C:11]2=[O:21])[CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10]([CH3:22])[C:11]2=[O:21])[CH2:3]1
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](C)C[C@@H]32)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](C)C[C@@H]32)C1

Procedure:
To a solution of 3β,16β-dimethylandrost-5-en-17-one prepared in Example I in 500 ml of ethanol is added 5% Pd on C and the mixture is exposed to a hydrogen atmosphere while stirring. The catalyst is filtered off and the above-identified product is isolated.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)CCC>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Yield: 102.5 %

Procedure:
A mixture of 65.6 g of ethyl 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinecarboxylate, 32.0 g of potassium hydroxide and 250 ml of n-butanol was refluxed for 2 hrs and concentrated. Water was added to the residue and extracted with toluene. The toluene layer was washed with water, dried and concentrated to give 53.2 g of pale yellow solid, which was recrystallized from methanol to give 47.9 g of colorless needles, mp 145°-147° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:25]=[C:24]4[C:19]([N:20]=[CH:21][C:22](=O)[NH:23]4)=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:22]1[CH:21]=[N:20][C:19]2[C:24](=[CH:25][C:16]([C:9]3[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)=[N:12][N:11]4[CH2:13][CH2:14][CH2:15][C:10]=34)=[CH:17][CH:18]=2)[N:23]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(=O)[nH]c4c2)CCC3)n1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(Cl)nc4c2)CCC3)n1
Yield: 86 %

Procedure:
Dissolve 7-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-one (Example 55b; 200 mg, 0.6 mmol) in phosphorus oxychloride (20 mL). Reflux the solution for 30 min. Evaporate in vacuo. Dissolve the residue in 3:1 chloroform/isopropyl alcohol (100 mL) and wash the solution with 5% aqueous ammonia solution, brine and water. Dry the organic phase over sodium sulfate. Filter and evaporate the solvents in vacuo to give the target product as a yellow solid 180 mg (86%). MS (electrospray, m/z) 362.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:16].[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)(=[O:10])=[O:9])=[CH:4][C:3]=2[F:16])=[CH:21][CH:20]=1)#[N:18]
Reactant: O=S(=O)(NC1CCC1)c1ccc(Br)c(F)c1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC2CCC2)cc1F
Reaction time: 16 h
Yield: 14.2 %

Procedure:
According to general procedure B, 4-bromo-N-cyclobutyl-3-fluorobenzenesulfonamide (182 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-3-fluorobenzenesulfonamide (28 mg, 14%) was provided after purification. HRMS: calcd for C16H16FN3O2S−H+, 332.08745; found (ESI, [M−H]−), 332.0867. HPLC purity 96.9% at 210-370 nm, 9.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].C=O.[OH-].[Na+].[C:14](O)(=O)C(O)=O>CO>[CH3:14][NH:3][C:2]1[N:4]=[C:5]([NH2:6])[N:7]=[C:8]([NH2:9])[N:1]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1nc(N)nc(N)n1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1nc(N)nc(N)n1
Temperature: 70 °C

Procedure:
C-2: A mixture of 378 parts by weight of melamine and 810 parts by weight of 37% formalin was adjusted to pH 7-8 with sodium hydroxide. The mixture was heated to about 70° C. and when it became transparent, 1800 parts by weight of methyl alcohol and 1.9 parts by weight of oxalic acid were added thereto. Then, the mixture was boiled for several minutes. The reaction mixture was cooled, then filtrated and concentrated under reduced pressure to obtain polymethoxy methyl melamine (C-2). An analysis showed that the number of methanol bonded was about 3 mols per 1 mol of melamine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[CH2:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2.[H-].[K+].[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>O1CCCC1>[CH3:8][C:5]1[C:4]([Si:22]([CH3:24])([CH3:23])[CH3:21])=[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(C)=C(c2cccc3cccnc23)C1
Reactant: C[Si](C)(C)Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1=C(C)C(C)C(c2cccc3cccnc23)=C1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 0.87 g (3.7 mmol) of 2,3,4-trimethyl-1-(8-quinolyl)cyclopentadiene in 20 ml of tetrahydrofuran was added to a suspension of 0.15 g (3.7 mmol) of potassium hydride in 30 ml of tetrahydrofuran and the mixture was subsequently stirred at room temperature for 6 hours. 0.402 g (3.7 mmol) of trimethylsilyl chloride was added while stirring and the mixture was stirred at room temperature for a further 12 hours. The volatile constituents were distilled off and the residue obtained in this way was distilled. At 126-136° C. and 2×10−2 mbar, 3,4,5-trimethyl-1-(8-quinolyl)-2-trimethylsilylcyclopentadiene distilled over in a yield of 0.455 g (1.5 mmol, 40%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:25])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]3[C:20]([C:21]=2[Cl:22])=[CH:19][CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1.CN(C=O)C>O>[CH:1]([O:4][C:5](=[O:25])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:15]3[C:20]([C:21]=2[Cl:22])=[CH:19][CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: BrCC1CC1
Reactant: COc1ccc2c(Cl)c(-c3ccc(NC(=O)OC(C)C)cc3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cl)c(-c3ccc(NC(=O)OC(C)C)cc3)n(CC3CC3)c2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
A mixture of [4-(3-Chloro-6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (50 mg, 0.14 mmol), Cs2CO3 (95 mg, 0.29 mmol), bromomethylcyclopropane (18 μL, 0.18 mmol), and DMF (200 μL) was stirred at 60° C. for 4 h. The reaction mixture was then stirred at room temperature for 1 h, diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (7:3 CH2Cl2/hexane) to provide [4-(3-chloro-1-cyclopropylmethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (19 mg, 33%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.FC(F)(F)S(O[C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[O:28][CH:29]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[O:28][CH:29]=[C:25]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4]([NH2:18])=[N:5][CH:6]=3)[N:26]=2)=[CH:35][CH:34]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: O=S(=O)(Oc1coc(-c2ccc(F)cc2)n1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2coc(-c3ccc(F)cc3)n2)cnc1N
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (200 mg, 0.8 mmol) and 2-(4-fluorophenyl)oxazol-4-yl trifluoromethanesulfonate (250 mg, 0.8 mmol), and 2.0 M aqueous Na2CO3 (1.2 mL, 2.4 mmol) in DME (2.0 mL) was sparged with Ar. Dichlorobis(triphenylphosphine)palladium(0) (281 mg, 0.4 mmol) was added and the reaction mixture was irradiated at 150° C. for 15 min in a microwave reactor. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over (SiO2, 100:0-0:100 hexanes-EtOAc) to provide 145 mg of 5-(2-(4-fluorophenyl)oxazol-4-yl)-3-methoxypyridin-2-amine: LCMS (m/z): 286.1 (MH+), tR=0.68 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].[H-].[Na+]>CN(C)C=O.[OH-].[Na+]>[CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH:7][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1cc(N)c([N+](=O)[O-])cc1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(NCCN(C)C)c([N+](=O)[O-])cc1OC
Temperature: 60 °C
Yield: 70 %

Procedure:
To a solution of 4,5-dimethoxy-2-nitroaniline (0.81 g) and 2-chloroethyldimethylamine hydrochloride (0.73 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (0.36 g) in small portions with ice-cooling and the reaction mixture was heated at 60° C. for 2 hours. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was successively washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:chloroform:methanol=15:1) to give 0.77 g of N-(4,5-dimethoxy-2-nitrophenyl)-N',N'-dimethylethylenediamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].I[CH:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH:19]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1)([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cnn(C(C)C)c2c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 55.9 %

Procedure:
A solution of methyl 1H-indazole-6-carboxylate (1.92 g, 10.9 mmol) and cessium carbonate (7.12 g, 21.8 mmol) in N,N-dimethylformamide (21.8 mL) under argon was heated to 60° C. for 10 min. 2-Iodopropane (1.09 mL, 10.9 mmol) was added dropwise. The mixture was stirred at 60° C. for 1.5 h. The mixture was cooled to ambient temperature and quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with saturated aqueous ammonium chloride (3×20 mL), saturated aqueous sodium chloride (1×20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (1.33 g): LC-MS [M+1]=219.2.
Reaction SMILES: [NH:1]1[CH2:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH2:2]1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23](OB(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20]>>[NH:1]1[CH2:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][C:8]2([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:19]([O:18][CH3:17])=[O:20])[CH:26]=3)[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]2)=[O:5])[CH2:2]1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: O=C(OCc1ccccc1)C1CCCNC1
Product: COC(=O)c1cccc(C2(COC(=O)C3CCCNC3)C=CC=CC2)c1
Yield: 32.9 %

Procedure:
Using benzyl nipecotate (4.39 g, 20.0 mmol) and 3-methoxycarbonylphenylboric acid (7.20 g, 40.0 mmol), the same procedure was followed as in Example 2 to give 2.34 g (33%) of the desired compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1(/[CH:17]=[C:18](\B2OC(C)(C)C(C)(C)O2)/[CH2:19][OH:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[F-].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1(P([Pd-4](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)C=CC=CC=1>[CH:11]1(/[CH:17]=[C:18](\[C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)/[CH2:19][OH:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(/C(=C\C2CCCCC2)CO)cc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
Add tetrakis(triphenylphosphino)palladium(0) (0.60 g, 0.52 mmol) to a solution of 1-bromo-4-nitro-benzene (0.76 g, 3.76 mmol) and (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.13 g, 4.24 mmol) in dioxane (20 mL). Add cesium fluoride (1.75 g, 12 mmol) and stir the reaction mixture for 12 h at 80° C. Allow the reaction mixture to cool to r.t. Dilute the reaction mixture with ethyl acetate and wash with water. Separate the layers. Dry the organic phase over sodium sulfate, filter and concentrate. Purify the residue via silica gel chromatography, eluting with a gradient from 95:5 to 7:3 hexanes:ethyl acetate to obtain the title compound (0.67 g). 1H-NMR (CDCl3) δ=1.05-1.72 (m, 10 H), 1.89-2.04 (m, 1H), 4.28-4.36 (m, 2H), 5.61-5.69 (m, 1H), 7.34-7.43 (m, 2H), 8.18-8.26 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C:10](=[O:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[B]1OC2C(=CC=CC=2)O1.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C)(C)CC2)c1Br
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [B]1Oc2ccccc2O1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C)(C)CC2)c1Br
Temperature: -30 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
To a yellow solution of isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (7.7 g, 18.72 mmol) and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (7.5 mL, 7.50 mmol) in anhydrous toluene (100 mL) was added drop wise 50% catecholborane/toluene (6 mL, 28.0 mmol) over 5 min at −50° C. Then, the reaction mixture was slowly warmed to −30° C. over 1 h and left in refrigerator (−20° C.) for 3 days. Then, the reaction mixture was diluted with EtOAc (100 mL) and 20 mL of 1M Na2CO3, and vigorously stirred for 30 min. Aqueous layer separated and organic layer washed with sat'd Na2CO3 (2×25 mL) by vigorously stirring for 15 each time, then dried (MgSO4), filtered and concentrated to give crude product as light purple paste which was purified by flash chromatography using 0 to 40% EtOAc/hex to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (6.7 g, 15.72 mmol, 84% yield) as colorless thick paste. 1H NMR (500 MHz, CDCl3) δ 5.85 (d, J=5.7 Hz, 1H), 5.59 (d, J=7.4 Hz, 1H), 5.08 (dt, J=12.5, 6.3 Hz, 1H), 3.98-3.88 (m, 1H), 3.88-3.78 (m, 1H), 2.76-2.68 (m, 1H), 2.67 (s, 3H), 2.64-2.58 (m, 1H), 2.57 (s, 3H), 1.73 (td, J=12.8, 4.8 Hz, 1H), 1.65-1.59 (m, 1H), 1.47-1.35 (m, 2H), 1.27 (d, J=6.3 Hz, 3H), 1.17 (d, J=6.1 Hz, 3H), 1.09 (s, 3H), 1.04 (s, 3H). LCMS (M+H)=414.6.