Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:19][CH:20]=2)[NH:15][N:14]=1.[CH2:26](Br)[CH:27]=[CH2:28]>CN(C=O)C>[CH2:28]([N:14]1[C:13]([C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][CH3:3])=[C:21]2[C:16]([C:17]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:19]=[CH:20]2)=[N:15]1)[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1OC
Reaction time: 8 h
Yield: 34.9 %

Procedure:
Sodium hydride (60% in oil, 0.025 g, 1.04 mmol) was added in one portion to a solution of 3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (0.150 g, 0.49 mmol) in DMF. After the gas evolution ceased, allyl bromide (0.07 mL, 0.7 mmol) was added and the reaction mixture was stirred at ambient temperature to 50° C. overnight. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The resulting residue was purified by flash chromatography or by HPLC chromatography through silica gel columns, 150×12 mm (Biotage, Charlottesville, Va.), at 10 mL/min with methyl-t-butyl ether/hexane (gradient elution, 1:9 to 1:1) to give the title compound (0.062 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:6]([F:8])([F:7])[C:5]([F:10])([F:9])[C:4]([F:12])([F:11])[C:3]=1Cl.C(N(CC)CC)C>CO.[Ni]>[F:7][C:6]1([F:8])[CH2:2][CH2:3][C:4]([F:12])([F:11])[C:5]1([F:9])[F:10]
Reactant: FC1(F)C(Cl)=C(Cl)C(F)(F)C1(F)F
Agent: [Ni]
Solvent: CO
Solvent: CCN(CC)CC
Product: FC1(F)CCC(F)(F)C1(F)F
Reaction time: 12 h
Yield: 59.5 %

Procedure:
In a 1.3 1 stainless steel autoclave, 245 g (1 mol) of 1,2-dichloro-3,3,4,4,5,5-hexafluorocyclopentene were hydrogenated at 60°to 70° C. with the addition of 202 g (2 mol) of triethylamine in 200 ml of methanol and in the presence of 20 g of Raney nickel. Over a period of 12 hours, the theoretical amount of hydrogen was absorbed at a hydrogen pressure of 40 to 50 bar. The reaction mixture was filtered and the methanolic solution was diluted with 400 ml of water. The lower organic phase was separated, washed with 100 ml of 5% aqueous hydrochloric acid, and dried over sodium sulfate. Distillation through a 1-m spinning band column gave 106 g (60% of theory) of 1,1,2,2,3,3-hexafluorocyclopentane having a boiling point of 87°-88° C. at 1013 mbar. The mass spectrum showed the molecular ion at m/e 178.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([C:28]([CH3:32])([CH3:31])[C:29]#[N:30])=[N:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:39].[Na+]>CC(O)C>[C:33]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([C:28]([CH3:32])([CH3:31])[C:29]([NH2:30])=[O:39])=[N:26][N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C#N)c1nnc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C(N)=O)c1nnc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 40 °C

Procedure:
409 mg of 2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionitrile was dissolved in 6 ml of 2-propanol; 3.5 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring under heating at an external temperature of 40° C. for 12 hours. After cooling, the 2-propanol was distilled off; the residue was extracted with ethyl acetate-tetrahydrofuran (1:1), washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized from ethyl acetate-diethyl ether (1:1), washed with diethyl ether, and dried, to yield 293 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.[F:25][C:26]([F:31])([F:30])[CH2:27][CH2:28]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])[N:16]=2)[N:13]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1n(CCC(F)(F)F)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (36 mg, 0.1 mmol), 1,1,1-trifluoro-3-iodopropane (67 mg, 0.3 mmol) and solid K2CO3 (42 mg, 0.3 mmol) in anhydrous DMF (0.6 mL) was stirred at room temperature for 2 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional 1,1,1-trifluoro-3-iodopropane (67 mg, 0.3 mmol) was added, the reaction was allowed to continue at room temperature for 16 h, then at 45° C. for 30 min. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated EtOAc layer was washed with water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-60%) in hexanes to yield a yellow oily product, which was lyophilized in acetonitrile to afford 38 mg (84%) of the title compound as a yellow powder. LC/MS (method A): retention time=3.69 min, (M+H)+=453. 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 7.21 (d,J=8.8 Hz, 2H), 7.05 (d,J=8.8 Hz, 2H), 4.36 (m, 2H), 2.76 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Mg].C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.S(=O)(=O)(O)O>C1COCC1.C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]([B:21]([OH:22])[OH:20])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(B(O)O)cc(C(C)(C)C)c1

Procedure:
3,5-Di-t-butylbromobenzene (10 g, 37 mmol) and magnesium (1.8 g, 75 mmol) were dissolved in 100 mL of THF and stirred at reflux for five hours. After this time, triisopropylborate (7.0 g, 37 mmol) as a solution in diethylether (50 mL) was added to the solution, followed by stirring at room temperature overnight. Then the THF was removed in vacuo to leave a crude oil. This oil was taken up in 100 mL of diethylether and 100 mL of 10% sulfuric acid (aqueous) and stirred for two hours. The organic layer was separated and neutralized with saturated sodium bicarbonate solution, whereafter the solvent was removed in vacuo to yield a white solid. The solid is washed generously with pentane. Yield: 3.0 g (34%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH2:24])[N:23]=3)[CH:20]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH:24][C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])[N:23]=3)[CH:20]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}carbamate (1.5 g, 4.39 mmol) in N,N-dimethylacetamide (5.0 mL) was added cyclopropanecarbonyl chloride (480 μL, 5.27 mmol) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.79 g, 99%) as a pale-yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].CO[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:16]1([O:24]C)[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:18]C.Cl.N1C=CC=CC=1>ClCCl>[OH:18][C:17]1[CH:20]=[C:21]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:22]=[CH:23][C:16]=1[OH:24]
Reactant: COC(=O)CCCC(=O)O
Reactant: COc1ccccc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)CCCC(=O)c1ccc(O)c(O)c1

Procedure:
Under the conditions of example 3A, 28.8g of aluminum chloride in 320 ml of dichloromethane is reacted with 11.9g of glutaric acid monomethyl ester chloride and 10g of veratrole, worked up and chromatographed. The thus obtained crude product is further reacted under the conditions of example 3A with 270g of pyridinehydrochloride and worked up. 5.6g of 5-(3,4-dihydroxyphenyl)- 5-oxo-pentanoic acid of melting point 210°-215° C. is obtained as crude product.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:27])([CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH3:20]>>[CH3:26][S:23]([CH2:22][CH2:21][C:19]([NH:27][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:20])[CH3:18])(=[O:25])=[O:24]
Reactant: CC(C)(N)CCS(C)(=O)=O
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(CCS(C)(=O)=O)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-methyl-4-(methylsulfonyl)-2-butanamine (CAN 1250515-16-2) as starting materials; LC-MS (UV peak area/ESI) 95%, 381.1843 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:12]2[C:13]([NH:15][C:16](=[O:17])[C:11]=12)=[O:14].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[N:21]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:20]=[CH:19][CH:18]=[C:12]3[C:13]([NH:15][C:16](=[O:17])[C:11]=23)=[O:14])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C1NC(=O)c2c(CCCCCCCCBr)cccc21
Reactant: C1COCCN1
Solvent: CC#N
Product: O=C1NC(=O)c2c(CCCCCCCCN3CCOCC3)cccc21

Procedure:
8-Bromooctylphthalimide (676 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous acetonitrile (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([NH2:17])[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([O:20]C=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([NH:17][CH:18]=[O:20])[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Reactant: CCOC=O
Product: CC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Reaction time: 24 h
Yield: 93 %

Procedure:
50 g (184.4 mmol) of 1-[1-(3,4-Dichloro-phenyl)-cyclohexyl]-ethylamine was dissolved in 1 L of ethylformate and left to stir under an N2 atmosphere for 24 h before removing all volatiles under reduced pressure. The resulting solid was filtered through a plug of SiO2 (using CH2Cl2/MeOH (20:1) as the eluent) to afford 51.32 g (93%) of the title compound after the removal of all volatiles. This material was used in the subsequent step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([Cl:30])=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[Cl:30][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:22]2[S:23][C:15]([CH:14]=[C:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:16][C:17]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Clc1nc(N2CCOCC2)c2sc(C=C3CCNCC3)cc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
To a suspension of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethylene)-piperidine-1-carboxylic acid tert-butyl ester (0.85 g) in dichloromethane (10 mL) at room temperature was added hydrogen chloride (2 mL of a 2.0 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 16 h and then reduced in vacuo. The residue was redissolved in dichloromethane (10 mL) and washed with saturated sodium carbonated solution (2×10 mL) and brine (10 mL), dried (MgSO4) and reduced in vacuo to give 2-chloro-4-morpholin-4-yl-6-piperidin-4-ylidenemethyl-thieno[3,2-d]pyrimidine (0.53 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[CH2:5][C:4]([CH3:20])([CH3:19])[NH:3]1.[CH3:22]SC[C@H](NC(CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)C(O)=O.C=O.C(O)=O.C(=O)=O>>[CH3:22][N:8]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[CH:6]1[CH2:7][C:2]([CH3:21])([CH3:1])[NH:3][C:4]([CH3:20])([CH3:19])[CH2:5]1
Reactant: CSC[C@H](NC(=O)CC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: C=O
Agent: O=C=O
Solvent: O=CO
Product: CN(C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Yield: 49 %

Procedure:
1. A 200 ml sulfonation flask is charged with 40.48 g (0.14 mol) of bis(2,2,6,6-tetramethyl-piperidin-4-yl)amine [EP-A-336 895, Ciba-Geigy] and 11.4 g (0.14 mol) of a 36% aqueous solution of formaldehyde. 25.8 g (0.56 mol) of formic acid are added dropwise at room temperature. The temperature in the flask rises to 70° C. with evolution of CO2. The reaction mixture is stirred until it has cooled to room temperature. The aqueous phase is then saturated with potassium carbonate and the reaction mixture is extracted three times with chloroform. The organic phases are combined, dried over potassium carbonate and concentrated on a vacuum rotary evaporator. Chromatography of the residue over silica gel using the solvent system hexane/dichloromethane 9:1+5% triethylamine gives 21 g (49%) of the methyl-bis(2,2,6,6-tetramethyl-piperidin-4-yl)amine, m.p. 51°-53° C., in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:22][CH2:23][F:24])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:22][CH2:23][F:24])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)cc(Cl)c1
Reactant: CS(=O)(=O)OCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(OCCF)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 3-chloro-5-hydroxybenzaldehyde (8.2 g, 52.5 mmol; see Preparation A(ii) above) and potassium carbonate (9.4 g, 68.2 mmol) in DMF (10 mL) under nitrogen was added a solution of (2-monofluoroethyl) methanesulfonate (9.7 g, 68.2 mmol; see step (i) above) in DMF (120 mL) dropwise at room temperature. The mixture was heated to 100° C. for 5 h and then stirred overnight at room temperature. The reaction was cooled to 0° C., poured into ice-cold 2N HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The brown oil was chromatographed on silica gel eluting with Hex:EtOAc (4:1) to afford the sub-title compound (7.6 g, 71%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5]2[C:7]([C:16]([OH:18])=[O:17])=[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]3=[CH:15][C:4]=2[O:3]1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:20][O:17][C:16]([C:7]1[C:8]2[O:12][C:11]([CH3:13])([CH3:14])[O:10][C:9]=2[CH:15]=[C:4]2[O:3][C:2]([CH3:19])([CH3:1])[O:6][C:5]=12)=[O:18]
Reactant: CC1(C)Oc2cc3c(c(C(=O)O)c2O1)OC(C)(C)O3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c2c(cc3c1OC(C)(C)O3)OC(C)(C)O2
Temperature: 55 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-carboxylic acid (10.0 g, 38.0 mmol) was dissolved in dry DMF (100 mL). Potassium carbonate (15.2 g, 110.0 mmol) was added and the reaction was heated to 55° C. for 30 min. After cooling to ambient temperature, methyl iodide (15.6 g, 110.0 mmol) was added and the solution was stirred overnight. The precipitate was filtered off and the solution was evaporated. The residue was dissolved in saturated aqueous NaHCO3 and ether. The aqueous layer was discarded and the organic phase was dried (Na2SO4), filtered and evaporated to give 9.4 g (88%) of the pure product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[N:7][CH:8]=1.[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>CCO>[CH2:12]([O:14][C:15]1[C:18](=[O:19])[C:17](=[O:22])[C:16]=1[NH:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1)[CH3:13]
Reactant: Nc1cncc(C(F)(F)F)c1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cncc(C(F)(F)F)c2)c(=O)c1=O
Yield: 38 %

Procedure:
A solution of the product from Example 52A (2.98 g, 18.4 mmol) and 3,4,-diethoxy-3-cyclobutene-1,2-dione (3.13 g, 18.4 mmol) in EtOH (50 mL) was heated at reflux for 48 hours. The reaction mixture was filtered while still hot and the filtrate was absorbed onto silica gel. The crude material was purified by chromatography, eluting with EtOAc/hexanes (3:1) to provide 2.00 g (38% yield) of the desired compound as colorless crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[C:44]1([N:50]=[C:51]=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:51]([NH:50][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:52])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: O=C=Nc1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)Nc2ccccc2)CC1

Procedure:
In a manner similar to the method described in example 160, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with phenyl isocyanate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H47Cl2N6O3 [(M+H)+] 741.3081, observed 741.3081.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][O:12][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC1(C#CCO)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC1(C#CCOCc2ccc3ccccc3c2)CCOCC1

Procedure:
4-methoxy-4-(3-hydroxyprop-1-ynyl)tetrahydropyran (1.2 g, 6.97 mmol) was treated with sodium hydride in THF (18 mL). After gas evolution ceased, a solution of 2-(bromomethyl)napthalene (1.70 g, 7.67 mmol) in dry DMF (9 mL) was added. After 3 hours at ambient temperature the reaction was quenched with saturated aqueous ammonium chloride. The resulting two-phase mixture was extracted with ether (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by chromatography on silica gel (100 g, 10% ethyl acetate: hexanes) provided the title compound. (2.00 g, 92%) as a colorless oil. 1H NMR (300 MHz, CDCl3); 7.80-7.90 (4H, m), 7.47-7.52 (3H, m), 4.70 (2H, s), 4.32 (2H, s), 3.87 (2H, dd, J=12,4.5 Hz), 3.67 (2H, dd, J=12,3 Hz), 3.40 (3H, s), 1.95 (2H, br d, J=13 Hz), 1.49 (2H, ddd, J=13,9,4.5 Hz); MS (M+NH4)+ =328. Analysis calc'd for C20H22O3 : C, 77.39; H, 7.14; Found: C, 76.10; H, 7.10.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][S:9][C:8]=1Br.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15]>O1CCCC1>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:8]1[S:9][C:10]([Sn:14]([CH3:16])([CH3:15])[CH3:13])=[CH:11][CH:7]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1ccsc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc([Sn](C)(C)C)s1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
After 18.4 mL (30 mmol) of n-butyl lithium solution (n-BuLi, 1.63M in hexane) was added to a solution of 3.0 g (12.4 mmol) dibromothiophene in tetrahydrofuran (50 mL) at −50° C. under nitrogen atmosphere, the reaction was allowed to proceed for 30 minutes. To the mixture was added 5 g of trimethylstannyl chloride (SnMe3Cl, 25 mmol) and the reaction was continued at −50° C. for about 4˜5 hours. Next, the aqueous layer and organic layer were separated. The obtained organic layer was dried over a drying agent, and then solvents were removed. The resulting crude product was recrystallized from ether twice to afford 3.1 g (yield: 60%) of the title compound as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:36][CH2:37][S:38][CH3:39])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:35][CH2:34][C@@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=1)=[O:22])[CH2:36][CH2:37][S:38][CH3:39]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CSCC[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol), (S)-2-amino-4-(methylthio)butan-1-ol (32 mg, 0.24 mmol), and HATU (90 mg, 0.24 mmol). Then added acetonitrile (4 mL) followed by N,N-diisopropylethylamine (0.19 mL, 1.1 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-50% EtOAc) to afford 105 mg (83%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methylsulfanyl-propyl)-amide as an off-white foam. MS: [M+H]+=559.