Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[CH:9]=1.[C-:13]#[N:14].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:13]#[N:14])[CH:9]=1
Reactant: COC(=O)Cc1cc(CCl)cs1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(CC#N)cs1
Temperature: 50 °C
Yield: 77.8 %

Procedure:
A solution of (4-chloromethyl-thiophen-2-yl)-acetic acid methyl ester (0.58 g, 2.83 mmol) and potassium cyanide (0.39 g, 5.95 mmol) in DMF (15 mL) is stirred at room temperature for 14 h then heated to 50° C. for 0.5 h. The mixture is quenched with saturated aq NaCl and extracted with CHCl3 (3×). The combined organic layers are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel, 10% ethyl acetate in heptane) to give (4-cyanomethyl-thiophen-2-yl)-acetic acid methyl ester (0.43 g, 78%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.10 (s, 1 H), 6.95 (s, 1 H), 3.80 (s, 2 H), 3.72 (s, 3 H), 3.65 (s, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][OH:20])([CH3:18])[CH2:13]3)[O:7][C:6]=2[CH:21]=1.[H-].[Na+].I[CH3:25].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][O:20][CH3:25])([CH3:18])[CH2:13]3)[O:7][C:6]=2[CH:21]=1
Reactant: C[C@]1(CO)CCCN(C[C@H]2COc3ccc(F)cc3O2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@]1(C)CCCN(C[C@H]2COc3ccc(F)cc3O2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
[(S)-1-((S)-7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]-methanol (2.5 g, 8.5 mmol) in tetrahydrofuran (10 ml) was added slowly to a mixture of sodium hydride, 60% in oil (1.354 g, 33.9 mmol) and tetrahydrofuran (15 ml). The reaction mixture was heated at 60° C. for 2 hours after the mixture was cooled down and iodomethane (0.685 ml, 11.0 mmol) in tetrahydrofuran (3 ml) was added. The mixture was stirred at RT for 1 hour, water (25 ml) was added carefully and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were evaporated to dryness. Ethyl acetate (20 ml) was added to the evaporation residue and was made acidic with aq HCl. The layers were separated and the water layer was made basic with aq NaOH and extracted twice with ethyl acetate. The combined ethyl acetate layers were evaporated to dryness to yield 2.34 g (89%) of the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:2][CH2:3][CH2:4][CH:5]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=c1onc2n1C(CCCO)CCCC2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1onc2n1C(CCCBr)CCCC2
Reaction time: 2 h

Procedure:
To a solution of the product of Example 11 in methylene chloride at 0° C. is added carbon tetrabromide and triphenylphosphine. The reaction is stirred for 2 hours and the solvent is removed under reduced pressure. The crude product is dissolved in an eluting solvent system and chromatographed to afford the title compound.
Reaction SMILES: I[Si](C)(C)C.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:13]1[CH2:22][CH2:21][CH2:20][C@@H:19]2[N:14]1[C:15](=[O:23])[CH2:16][CH2:17][CH2:18]2.CN(C)CCN(C)C.[I:32]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:13]1[CH2:22][CH2:21][CH2:20][C@@H:19]2[N:14]1[C:15](=[O:23])[CH:16]([I:32])[CH2:17][CH2:18]2
Reactant: II
Reactant: O=C1CCC[C@@H]2CCC[C@H](c3ccccc3F)N12
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1C(I)CC[C@@H]2CCC[C@H](c3ccccc3F)N12
Yield: 107.2 %

Procedure:
Iodotrimethylsilane (0.28 mL) was added to a solution of (6R*,9aS*)-6-(2-fluorophenyl)octahydroquinolizin-4-one (309 mg) and N,N,N′,N′-tetramethylethylenediamine (0.66 mL) in methylene chloride (12 mL) under ice-cooling in a nitrogen atmosphere, and the reaction solution was stirred under ice-cooling for 30 minutes. Iodine (476 mg) was added to the reaction solution under ice-cooling, and the reaction solution was stirred under ice-cooling for one hour. Ethyl acetate and a saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 500 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14](OS(C)(=O)=O)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([F:21])[CH:23]=3)[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Product: O=C(O)c1cc(Cl)cnc1N1CC(Nc2cccc(F)c2)C1
Yield: 33.2 %

Procedure:
The title compound (D116) (40 mg) was prepared according to the experimental procedure described in Description 115 starting from methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63) (120 mg, 0.374 mmol) and 3-Fluoroaniline (0.036 ml, 0.374 mmole).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>CCOCC>[CH2:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)=[CH:3][CH:4]=1)[CH3:10]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOc1ccc(Br)cn1
Solvent: CCOCC
Product: CCOc1ccc(C2(O)CCC3(CC2)OCCO3)cn1

Procedure:
The title compound was prepared as a white solid from 5-bromo-ethoxy-pyridine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]=[CH:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][N+:17]([O-:19])=[O:18])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]2[CH2:14][CH2:15][N:11]([CH:10]=[N:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)[C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:23][N:22]=1
Reactant: Cc1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1C
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(N=CN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])cc1C
Temperature: 70 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A mixture of 71,0 g of 1-(3,4-dimethylphenyliminomethyl)-2-nitroiminoimidazolidine, 48.5 g of 2-chloro-5-chloromethylpyridine, 50.0 g of potassium carbonate and 200 g of dimethylsulfoxide was agitated at 70° C. for 1 hour. After cooling to room temperature, about 800 ml of water and about 200 ml of ethyl acetate were added to the reaction mixture, followed by agitation, separation into settled crystals and a filtrate, washing with water, drying and recrystallization of a combination of the crystals with those obtained by concentration to about 1/5 from about 400 ml of acetonitrile to give 41 g of 1-(2-chloropyridine-5-ylmethyl)-2-nitroimino-3-(3,4-dimethylphenyliminomethyl)imidazolidine.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH2:8]([O:10][C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[C:15](Cl)=[N:14][CH:13]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:8]([O:10][C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[N:14][CH:13]=1)[CH3:9]
Reactant: C[C@@H]1CNCCN1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(N2CCN[C@H](C)C2)c(Cl)c1

Procedure:
Heat a solution of (R)-2-methyl-piperazine (0.07 mol), 5,6-dichloro-nicotinic acid ethyl ester (TCI America) (10.1 g, 0.046 mol) and potassium carbonate (31.7 g, 0.23 mol) in DMA at 110° C. for 48 h. Cool the solution, and partition between EtOAc and brine. Separate the layers and extract the aqueous portion with EtOAc (1×). Wash the combined organic layers with 10% NaOH (4×), dry (Na2SO4), and concentrate under reduced pressure to give an oil which crystallizes on standing.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[CH3:14][CH2:15][O:16][C:17](OCC)(OCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:17]([O:16][CH2:15][CH3:14])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reaction time: 18 h

Procedure:
35.0 g (0.2 mol) of 1-acetyl-2-indolinone are dissolved in 300 ml of acetic anhydride and after the addition of 135 g (0.6 mol) of triethyl orthobenzoate the mixture is refluxed for 22 hours. The solvent is distilled off and the residue diluted with petroleum ether. After 18 hours' standing at ambient temperature, the crystalline precipitate is suction filtered, washed and dried.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][N:11]([CH3:19])[C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.C(O)C>COCCOC>[CH3:10][N:11]([CH3:19])[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:18]=2)[CH:17]=1
Reactant: CN(C)c1ccc(N)nc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1cn2cc(N(C)C)ccc2n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
215 μl of ethyl bromopyruvate are added to a suspension of 0.2 g of 5-dimethylaminopyridine-2-amine in 3 ml of DME. The reaction mixture is stirred at 20° C. for 16 hours, then, after addition of 3 ml of ethanol, for 16 hours at reflux and, finally, concentrated under reduced pressure. The residue is filtered on a cartridge comprising 15 g of silica, elution being carried out with a mixture of dichloromethane and methanol (98/2). The fractions comprising the expected product are combined and washed with a saturated sodium bicarbonate solution. The organic phase is dried and concentrated to dryness under reduced pressure to give 76 mg of ethyl 6-dimethylamino-imidazo[1,2-a]pyridine-2-carboxylate in the form of a green oil used as is in the continuation of the synthesis.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C@@H:18]([CH2:21][CH3:22])[CH2:19]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][C@@H:18]([CH3:19])[CH2:21][CH3:22])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC[C@H](C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC[C@H](C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 41 %

Procedure:
3.75 g of 4-hydroxybiphenyl-4'-carboxylic acid was heated under reflux together with (S)-2-methylbutyl alcohol in the presence of 0.10 g of p-toluenesulfonic acid for about 6 hours. Then the mixture was filtered to remove the unreacted 4-hydroxybiphenyl-4'-carboxylic acid. Next, the filtrate was evaporated and the unreacted (S)-2-methylbutyl alcohol was distilled off. The crystals thus obtained were recrystallized from 200 ml of n-hexane. Thus, 2.05 g of the corresponding colorless compound was obtained (Yield: 41%).
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[S:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][N:7]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:15]2[CH2:16][CH2:17][CH:12]([N:2]([CH3:1])[C:3]3[S:4][C:5]([C:8]([F:11])([F:9])[F:10])=[N:6][N:7]=3)[CH2:13][CH2:14]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CN(c1nnc(C(F)(F)F)s1)C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(c1nnc(C(F)(F)F)s1)C1CCN(Cc2ccc(F)cc2)CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A mixture of methyl-piperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D2) (0.050 g, 0.19 mmol), 4-fluorobenzyl chloride (0.029 ml, 0.24 mmol) and diisopropylethylamine (0.050 ml, 0.28 mmol) in acetonitrile (3 ml) was stirred at 120° C. for 30 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 0-1.5% ammonia in methanol (7M)/dichloromethane) to yield E1 (0.061 g, 87%) as a solid. C16H18F4N4S requires 374. Found 375 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:13]2[CH2:14][O:15]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: ClCC1CO1
Reactant: N#Cc1ccc(O)cc1Cl
Product: N#Cc1ccc(OCC2CO2)cc1Cl

Procedure:
The title compound was prepared from 2-chloro-4-hydroxy-benzonitrile and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C@H:20]([OH:23])[C:19]2=[O:24])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26].C(N(CC)CC)C.O>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C@H:20]([O:23][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=3)(=[O:35])=[O:36])[C:19]2=[O:24])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COCOc1ccc(N2CC[C@H](O)C2=O)nc1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COCOc1ccc(N2CC[C@H](OS(=O)(=O)c3cccc([N+](=O)[O-])c3)C2=O)nc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
2.2 g of 2-benzyl-3-methoxymethyloxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine (Example 138a) was dissolved in 20 ml of ethyl acetate, and 2.3 g of 3-nitrobenzenesulfonyl chloride, 183 mg of 4-dimethylaminopyridine and 3 ml of triethylamine were added thereto, followed by stirring at room temperature overnight. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 25-33% ethyl acetate/hexane as an eluent, to give 3.5 g of the target compound.
Reaction SMILES: [OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.[C:17]([NH:20][NH:21][C:22]([C:24]1[N:29]=[C:28]([N:30]2[CH2:34][CH2:33][CH2:32][CH:31]2[C:35]2[O:39][N:38]=[C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[CH:36]=2)[N:27]=[C:26]([NH:46][CH:47]2[CH:51]=[C:50]([CH3:52])[NH:49][N:48]2C(=O)C)[CH:25]=1)=O)(=[O:19])[CH3:18]>C1COCC1>[CH3:18][C:17]1[O:19][C:22]([C:24]2[N:29]=[C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH:31]3[C:35]3[O:39][N:38]=[C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)[CH:36]=3)[N:27]=[C:26]([NH:46][C:47]3[CH:51]=[C:50]([CH3:52])[NH:49][N:48]=3)[CH:25]=2)=[N:21][N:20]=1
Reactant: CC(=O)NNC(=O)c1cc(NC2C=C(C)NN2C(C)=O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(-c3nnc(C)o3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
(Methoxycarbonylsulfamoyl)triethylammonium hydroxide (internal salt) (90 mg, 3.76 mmol) was added to a solution of 6-[N-(acetylamino)carbamoyl]-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(2-acetyl-5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 51) (500 mg, 0.94 mmol) in anhydrous THF (20 ml) and the reaction heated at reflux for 18 hours. The volatiles were removed by evaporation and the residue was dissolved in methanol (5 ml) and 2N aqueous sodium hydroxide solution (11.0 ml) and stirred at ambient temperature for 15 minutes. The methanol was removed by evaporation and the pH of the resulting solution adjusted to pH 7 with 1N hydrochloric acid. The volatiles were removed evaporation and the residue purified by chromatography on silica gel eluting with DCM/methanol (100:0 increasing in polarity to 90:10). The purified product was then triturated with diethylether and collected by filtration to give the title compound (200 mg, 52%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.ClC1C=[C:41]2[C:47]([C:48]3[CH:49]=[C:50](NC(C(C)C)C(NCC(F)(F)F)=O)[CH:51]=[N:52][CH:53]=3)=CN(COCC[Si](C)(C)C)C2=NC=1.C(N)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:53]([NH:52][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1)[C:48]1[CH:47]=[CH:41][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Reactant: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: NCc1ccccc1
Product: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(NCc4ccccc4)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a nitrogen gas purged microwave vial of N2-[5-(5-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamide, 2-1a (1380 mg, 2.482 mmol), palladium(II) acetate (80 mg, 0.356 mmol) and (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (188 mg, 0.339 mmol) in DME (5 mL) was added benzylamine (0.407 mL, 3.72 mmol) followed by 1M lithium bis(trimethylsilyl)amide/THF (3.72 mL, 3.72 mmol). The reaction mixture was sealed and heated in an oil bath at 100° C. in a sealed microwave vessel for 18 h. An additional amount of palladium(II) acetate (80 mg, 0.356 mmol) and (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (188 mg, 0.339 mmol), benzylamine (0.407 mL, 3.72 mmol) followed by 1M lithium bis(trimethylsilyl)amide/THF (3.72 mL, 3.72 mmol) was added and the reaction was allowed to stir at 100° C. for 2 h. The reaction was quenched with aq. KHSO4, diluted with ethyl acetate. The organic layer was washed with aq. NaHCO3, dried over sodium sulfate, filtered and concentrated to an oil. The oil purified on silica gel (EtOAc/hexane; 50-100%) to afford the title compound, 5-1a.
Reaction SMILES: [CH:1]([C:4]([CH:15]([CH3:17])[CH3:16])=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[O:6][CH3:7])([CH3:3])[CH3:2].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.C(N(CC)CC)C>[C:18]([O:14][C:10]1[CH:9]=[C:8]([C:5]([O:6][CH3:7])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:12][CH:11]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=C(C(C)C)C(C)C)c1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=C(C(C)C)C(C)C)c1cccc(OC(=O)C(C)(C)C)c1
Reaction time: 3 h

Procedure:
Alkene 1b (2 g, 8.6 mmol) was dissolved in 50 mL of dry CH2Cl2 with 2.4 mL of anhydrous triethylamine. The flask was purged with argon and cooled in an ice bath. Pivaloyl chloride (1.6 g, 2 eq.) was added dropwise over one hour. The cooling bath was removed and stirring continued for 3 hours at room temperature. The solution was washed with aq. K2CO3 and then water, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel, eluting with 5% triethylamine in hexane yielding 1.95 g of dioxetane 1e: 1H NMR (CDCl3) δ 7.34-6.98 (m, 4H), 3.198 (s, 3H), 2.47 (sept, 1H), 2.33 (sept, 1H), 1.36 (s, 9H), 1.24 (d, 6 H, J=6.9 Hz), 0.92 (d, 6 H, J=6.9 Hz).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:23]2[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>>[F:26][C:27]([F:41])([F:42])[C:28]1[CH:29]=[C:30]([C:2]2[O:6][C:5]([CH2:7][N:8]3[C:16]4[C:11](=[C:12]([C:19]([F:20])([F:22])[F:21])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=4)[CH:10]=[C:9]3[CH:23]3[CH2:25][CH2:24]3)=[CH:4][CH:3]=2)[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(Br)o2)c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 310D using (1-[(5-bromo-2-furanyl)methyl]-2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 310C) and [3,5-bis(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 543 (M+1).
Reaction SMILES: [CH2:1]([Si:3]([CH2:11][CH3:12])([CH2:9][CH3:10])[C:4]#[C:5][CH2:6][CH2:7][OH:8])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:8][CH2:7][CH2:6][C:5]#[C:4][Si:3]([CH2:1][CH3:2])([CH2:9][CH3:10])[CH2:11][CH3:12])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[Si](C#CCCO)(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[Si](C#CCCOS(=O)(=O)c1ccc(C)cc1)(CC)CC
Yield: 102.5 %

Procedure:
A solution of 4-(triethylsilyl)but-3-yn-1-ol (2 mL; 9.22 mmol), p-toluensulfonyl chloride (3.52 g; 18.44 mmol) and pyridine (1.49 mL; 18.44 mmol) in dichloromethane (30 mL) was stirred at room temperature for 3 days. The reaction mixture was then washed with a saturated solution of sodium hydrogen sulphate and brine. The organic layer was dried, concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to yield 3.20 g (quantitative yield) of 4-(triethylsilyl)but-3-ynyl 4-methylbenzenesulfonate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([Si:19]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(F)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a solution of (4-fluoro-phenyl)-methanol (12.16 g, 96.4 mmol, 1.0 equiv) in anhydrous DMF (50 mL) at 0° C. under Ar was added imidazole (7.22 g, 106.1 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane (15.99 g, 106.1 mmol, 1.1 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 18 h at rt. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with a sat. solution of Na2CO3 (2×100 mL) and NaCl (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure yielding a brown oil that was purified by high vacuum distillation (bp 32-35° C. at 0.1 mbar) to give 23.0 g (99%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 0.00 (s, 6H), 0.84 (s, 9H), 4.60 (s, 2H), 6.89-6.94 (m, 2H), 7.16-7.20 (m, 2H). MS (EI): 183.1 [M-tert-Bu]+.