Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=1)=[O:2].[Cl:17]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:17][C:6]1[S:5][C:4]([NH:3][CH:1]=[O:2])=[N:8][C:7]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=CNc1nc(CSc2ccncc2)cs1
Solvent: CC(=O)O
Product: O=CNc1nc(CSc2ccncc2)c(Cl)s1
Reaction time: 5 h
Yield: 46.7 %

Procedure:
A mixture of 2-formylamino-4-(4-pyridylthiomethyl)thiazole (1.6 g) and N-chlorosuccinimide (1.5 g) in acetic acid (25 ml) was headed at 40°-50° C. for 5 hours with stirring and then the mixture was allowed to stand at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with aqueous sodium bicarbonate. The precipitates were collected by filtration washed with water and dried in vacuo to give 5-chloro-2-formylamino-4-(4-pyridylthiomethyl)thiazole (0.85 g, yield: 46.8%).
Reaction SMILES: [F:1][B-](F)(F)F.[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([N+]#N)=[CH:21][CH:20]=[C:19]([N:25]([C:29](=[O:31])[CH3:30])[CH:26]3[CH2:28][CH2:27]3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[CH3:7]>C1(C)C=CC=CC=1>[C:29]([N:25]([CH:26]1[CH2:28][CH2:27]1)[C:19]1[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH2:12][CH2:13]2)[C:22]([F:1])=[CH:21][CH:20]=1)(=[O:31])[CH3:30]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2[N+]#N)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2F)CC1
Yield: 39.1 %

Procedure:
To 800 ml of refluxing toluene was added in portions, as a solid, 46.2 g (0.1 mole) of 2-[4-(ethoxycarbonyl)-1-piperazinyl]-6-(acetylcyclopropylamino)-3-pyridinediazonium tetrafluoroborate. After the addition was complete, the reaction was refluxed for ten minutes and the toluene was decanted from the insoluble precipitate. The toluene was evaporated in vacuo and the residue was partitioned between chloroform and water. The chloroform layer was washed with 5% aqueous sodium bicarbonate, water, dried over magnesium sulfate and evaporated in vacuo to give 13.7 g of the title compound, as a viscous oil. An additional 10.2 g could be obtained by partitioning the original toluene insoluble material in chloroform and water. The organic layer was washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform/ethyl acetate (6:4). This fraction was also a viscous oil which did not crystallize upon standing. Both fractions were of sufficient purity to be used as is in the ensuing steps.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C@H:16]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](O)[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:15][C@@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Oc1cccnc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1cncc(O[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
DIAD (0.631 mL, 3.20 mmol) in DCM (5 ml) was added dropwise to a mixture of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol), pyridin-3-ol (305 mg, 3.20 mmol) and triphenylphosphine (840 mg, 3.20 mmol) in DCM (20 ml), cooled in an ice bath. The mixture was allowed to warm to room temperature, stirred for 1 hour and then concentrated. The residue was dissolved in dioxan (15 mL) and 4M HCl in dioxan (15 mL) was added. The mixture was stirred for 1 hour and concentrated. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol and pure fractions were evaporated to dryness to afford (3R)-3-(pyridin-3-yloxy)pyrrolidine (405 mg, 92%) as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>CN1CCCC1=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:29]([O:28][C:27](=[O:33])[NH:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:3]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cc1ccc(Nc2cc(Cl)nnc2C(N)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)cc1
Temperature: 150 °C
Yield: 7.8 %

Procedure:
6-Chloro-4-p-tolylamino-pyridazine-3-carboxylic acid amide (199 mg, 0.758 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (325 mg, 1.52 mmol) were dissolved in N-methylpyrrolidinone (4.7 mL). The reaction mixture was heated at 150° C. for 16 h, then additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (550 mg, 2.57 mmol total) was added in three portions over 6 d. The reaction mixture was cooled, diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, then dried (sodium sulfate), filtered, and concentrated in vacuo. The residue obtained was purified by chromatography (silica, 0 to 5% methanol in dichloromethane) to give [(1S,2R)-2-(6-carbamoyl-5-p-tolylamino-pyridazin-3-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (26 mg, 8%) as a light brown amorphous residue. LCMS (EI/CI) m/z: 441 [M+H].
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C[CH2:31][N:32](CC)CC.CN.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:32][CH3:31])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and methyl amine (0.32 mL, 2.0 M solution in THF, 0.65 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 80 mg (78%) of the title compound as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([F:19])[C@H:10]1[OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([F:19])[C:10]1=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@H](F)[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2C(F)C1=O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a solution of (±)-(1S,2S,3R)-3-tert-butoxycarbonylamino-1-fluoro-1,2,3,4-tetrahydro-2-naphthalenol (140mg) in anhydrous methylene chloride (5 ml) was added Dess-Martin periodinane (340 mg) and tert-butyl-alcohol (70 mg). Stirring was maintained at room temperature for 31/2 hours. The reaction was quenched with isopropanol and the reaction mixture was poured on a silica gel column (50 g, elution with cyclohexane: ethyl acetate, 9:1) to afford the title compound (105 mg) as an oil. Step G: 3-Amino-1-fluoro-3,4-dihydro-2(1H)-naphthalenone. hydrochloride
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][C:16]2[O:20][C:19]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[F:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][C:16]2[O:20][C:19]([CH2:21][C:22]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=4)[O:24][N:23]=3)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(F)cc2)o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Cc3ccc(F)cc3)o2)no1
Temperature: 25 °C
Reaction time: 19 h
Yield: 6.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 and (5-(4-fluorobenzyl)-furan-2-yl) acetohydroximoyl chloride (181 mg, 0.677 mmol) described in Manufacturing Example 208-1-5 was added triethylamine (147 μL, 1.06 mmol), which was stirred for 19 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2) to obtain the title compound (9 mg, 6%).
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].O.[OH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[C:26]2[CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:21][CH:20]=1>ClCCl>[CH3:11][S:8]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[C:26]([CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])[CH:25]=[CH:24][CH:23]=2)[CH:28]=1)(=[O:10])=[O:9]
Reactant: CC(=O)NCCc1cccc2ccc(OCCCO)cc12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1cccc2ccc(OCCCOS(C)(=O)=O)cc12
Temperature: -10 °C

Procedure:
In a 250 ml round-bottomed flask, the alcohol obtained in Step A is dissolved in 50 ml of dichloromethane, and 0.012 mol of triethylamine is added. The mixture is cooled in an ice/salt bath at −10° C., and then 0.012 mol of mesyl chloride is added dropwise with stirring with a magnetic stirrer. The reaction mixture is stirred at room temperature for 4 hours. 100 ml of water are then added, followed by extraction with CH2Cl2. The organic phase is washed with water, dried over MgSO4 and evaporated under reduced pressure. The resulting oil is purified by chromatography over silica gel (eluant: acetone/cyclohexane ({fraction (2/8)})).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:22][O:23][CH:24]([CH3:26])[CH3:25])[NH:14][C:15]=1[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])([CH3:10])[CH3:9].[C:27]([N:46]1[C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]2[CH:64]=[CH:63][C:60]([CH2:61]Br)=[CH:59][CH:58]=2)=[N:49][N:48]=[N:47]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C(=O)C.C(OCC)(=O)C>[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:22][O:23][CH:24]([CH3:26])[CH3:25])[N:14]([CH2:61][C:60]2[CH:59]=[CH:58][C:57]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=3[C:50]3[N:46]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:47]=[N:48][N:49]=3)=[CH:64][CH:63]=2)[C:15]=1[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])([CH3:9])[CH3:10]
Reactant: CC(C)OCc1nc(C(C)(C)O)c(C(=O)OC(C)C)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)OCc1nc(C(C)(C)O)c(C(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
239 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 550 mg of isopropyl 4-(1-hydroxy-1-methylethyl)-2-isopropoxymethylimidazole-5-carboxylate [prepared as described in Preparation 46(iii)] in 6 ml of N,N-dimethylacetamide, and the resulting mixture was stirred for 30 minutes. A solution of 1.62 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 10 ml of N,N-dimethylacetamide was then added dropwise, and the mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was mixed with water and ethyl acetate and shaken. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.47 g of the title compound as an amorphous powder.
Reaction SMILES: [N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[C:19](Cl)=[C:18]4[C:13]([N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:15](=[O:23])[N:16]([CH3:22])[C:17]4=[O:21])=[CH:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:30]1([OH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[C:19]([O:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:18]4[C:13]([N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:15](=[O:23])[N:16]([CH3:22])[C:17]4=[O:21])=[CH:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Oc1ccccc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-n4cncn4)cc3)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Oc3ccccc3)n(Cc3ccc(-n4cncn4)cc3)cc21
Temperature: 150 °C
Yield: 58.6 %

Procedure:
Crude 6-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-chloro-1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (12 mg, 0.029 mmol), phenol (14 mg, 0.15 mmol) and Cs2CO3 (29 mg, 0.087 mmol) are placed in a microwave vial, and then dioxane (0.25 mL) is added. The vial is sealed and heated in a Biotage microwave instrument at 150° C. for 3 h. The reaction mixture is then purified with a semi-preparative HPLC to give 8.0 mg of product as off-white solid (purity: 97%). MS (ESI) m/z 471.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[NH2:33]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[CH3:26])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CC1CCCCC1N
Solvent: c1ccccc1
Product: CC1CCCCC1NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2-methylcyclohexylamine (0.620 g, 5.48 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-methylcyclohexyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.373 g, 28.4% yield).
Reaction SMILES: [C:1]([OH:7])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[C:19]=1[C:20](Cl)=[O:21]>ClCCl>[CH3:3]/[C:2](=[CH:4]/[CH3:5])/[C:1]([O:7][C:20](=[O:21])[C:19]1[C:23]([Cl:28])=[CH:24][C:25]([Cl:27])=[CH:26][C:18]=1[Cl:17])=[O:6]
Reactant: C/C=C(/C)C(=O)O
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C/C=C(/C)C(=O)OC(=O)c1c(Cl)cc(Cl)cc1Cl
Temperature: 2 °C
Reaction time: 0.75 h
Yield: 32.8 %

Procedure:
Angelic acid (601 mg, 6.0 mmol) was dissolved in dichloromethane (3.0 mL) under argon. Diisopropylethylamine (1.23 mL, 7.20 mmol) was added at 5-10° C. in a period of 1 min. To this solution was added 2,4,6-trichlorobenzoyl chloride (1.12 mL, 7.20 mmol) at 3-6° C. in a period of 4 min. After the reaction solution had been stirred at 2° C. for 45 min, petroleum ether (9.0 mL) was added. The obtained suspension was purified by flash chromatography (petroleum ether/dichloromethane 3:1), giving the title compound as a white solid (605 mg, 33%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25]#[C:26][C:27]2[C:35]3[C:30](=[N:31][CH:32]=[N:33][C:34]=3[NH2:36])[NH:29][N:28]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.[C:37]([N:44]1[CH2:48][CH2:47][CH:46]([CH2:49]O)[CH2:45]1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH2:49][CH:46]3[CH2:47][CH2:48][N:44]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:45]3)[N:28]=[C:27]([C:26]#[C:25][C:19]3[CH:18]=[C:17]([O:16][CH3:15])[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=3)[C:35]=12
Reactant: COc1cc(C#Cc2n[nH]c3ncnc(N)c23)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C#Cc2nn(CC3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DIAD (197 μl) was added to a suspension of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (148 mg) obtained in Example 1 (Step 1), N-Boc-3-hydroxymethylpyrrolidine (154 mg), polymer supported triphenylphosphine (up to 3.0 mmol/g, 334 mg) in THF (5.0 ml), followed by stirring at room temperature for 3 hours. The insoluble matter was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, amorphous substance (94.5 mg). Physical properties: m/z [M+H]+ 479.1
Reaction SMILES: [F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([C:11]#N)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[OH-:16].[K+].[OH2:18]>C(O)C>[F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:18])=[O:16])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: [OH-]
Reactant: N#Cc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Yield: 85 %

Procedure:
A mixture of 4-pentafluoroethyl-benzonitrile (2.98 g, 13.5 mmol) and potassium hydroxide (3.03 g, 54.0 mmol) in water (40 mL) and ethanol (20 mL) was heated at reflux for 16 h. After cooling, the solution was partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced the title compound (2.76 g, 85%). White solid, MS (ISP) 238.9 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:15]2[C:26]2[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][NH2:37]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:15]2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:37][CH3:36])[N:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)ccn2C2CCN(Cc3ccccc3)CC2)n1
Solvent: C1CCOC1
Product: CNc1nccc(-c2c(-c3ccc(F)cc3)ccn2C2CCN(Cc3ccccc3)CC2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A mixture of 1.19 g (2.43 mmol) of 1-(1-benzylpiperidin-4-yl)-3-(4-fluorophenyl)-2-(2-methanesulfonylpyrimidin-4-yl)-1H-pyrrole [prepared as described in Step 42(ii) above] and 13 ml of a 2M solution of methylamine in tetrahydrofuran was stirred at 100° C. for 30 minutes in a sealed tube. At the end of this time, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:2 by volume mixture of hexane and ethyl acetate as the eluant to give 260 mg (yield 24%) of the title compound as a yellow amorphous solid.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]1[C:12](OCC)=[O:13].[NH3:18]>C(O)C>[CH3:2][C:3]1([CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]1[C:12]([NH2:18])=[O:13]
Reactant: N
Reactant: CCOC(=O)C1Nc2ccccc2C1(C)C
Agent: Cl
Solvent: CCO
Product: CC1(C)c2ccccc2NC1C(N)=O

Procedure:
The solution of 1 g of ethyl 3,3-dimethylindoline-2-carboxylate hydrochloride in 25 ml of ethanol is saturated with anhydrous ammonia and heated in a closed vessel to 50° for 4 days. It is evaporated, the residue crystallized from diethyl ether, suspended in water and 3N aqueous sodium hydroxide is added to render the mixture basic. It is extracted with methylene chloride, the extract dried and evaporated, to yield the 3,3-dimethylindoline-2-carboxamide melting at 156°-158°.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1)[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:49]([CH2:47][CH3:48])[C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNc1ccc(C)cc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CC)c2ccc(C)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-ethyl-p-toluidine (VWR) to give the title product. LC-MS (ES+) 782 [(M+H)+].