Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH3:13])/[CH2:11][OH:12])=[CH:5][CH:4]=1)[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.ClCCl>[C:14]([O:12][CH2:11]/[C:10](/[CH3:13])=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc(/C=C(\C)CO)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(/C=C(\C)COC(C)=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1790 %

Procedure:
(E)-3-(4-Ethylphenyl)-2-methyl-2-propen-1-ol (4.6 g, 26 1 mmol, obtained by LiAlH4 reduction of (E)-3-(4-ethylphenyl)-2-methyl-2-propenal as described for (E)-2-Ethyl-3-(4-methylphenyl)-2-propen-1-ol) was added to a mixture of acetic anhydride (4.0 g, 39 mmol), pyridine (3.5 g, 44 mmol) and DMAP (0.46 g, 3.7 mmol) in 50 ml of dichloromethane. The mixture was stirred for 20 hours at room temperature. The dichloromethane was removed on a rotary evaporator, and the residue dissolved in EtOAc. This solution was washed with aqueous 10% HCl, aqueous 10% NaOH, and saturated aqueous NaCl. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by silica gel flash chromatography (hexane/EtOAc=80:20) followed by Kugelrohr distillation (140-160° C., 0.05 mbar) yielding 3.9 g (17.9 mmol, 69% yield) of the product as a colorless oil.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([Si:15](C)([CH3:17])[CH3:16])C=C.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]([O:11][Si:15]([CH3:17])([CH3:16])[CH3:12])=[CH:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[Si](C)(C)C
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CC=C(O[Si](C)(C)C)CC1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
Into a two-necked flask were placed 4-tert-butylcyclohexanone (74.1 mg, 0.480 mmol), and toluene (5.0 ml) as a solvent, and the mixture was subjected to heating under reflux conditions under an argon atmosphere. After the start of the refluxing, allyltrimethylsilane (82.3 mg, 0.720 mmol) was added, and a solution (0.1 M) of triflic imide (1.35 mg, 4.80 μmol) in toluene was added dropwise. After 5 min, triethylamine (0.486 mg, 4.80 μmol) was added, and the mixture was reacted for 10 min. Thereafter, cooled aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with hexane and dried over sodium sulfate. The solvent was evaporated under reduced pressure and purified by column chromatography to give the object product 4-tert-butyl-1-trimethylsilyloxy-1-cyclohexene (yield 88%).
Reaction SMILES: [Br:1][C:2]1[N:22]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([OH:21])=O)=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[N:22]=[C:5]2[CH:6]=[C:7]([NH:10][C:11]([C:13]3[N:17]([CH3:18])[N:16]=[CH:15][C:14]=3[C:19]([N:23]3[CH2:26][CH2:25][CH2:24]3)=[O:21])=[O:12])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(Br)nc2c1
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A mixture of 5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (929 mg, 2.54 mmol), azetidine (206 μl, 3.05 mmol), propylphosphonic anhydride (50% in ethyl acetate, 3.75 ml, 6.36 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.63 mmol) in tetrahydrofuran (20 ml) was stirred for 18 hours at 25° C. The solvent was evaporated, the residue was triturated with sat. sodium hydrogencarbonate solution. The solid was filtered off, washed with water and dried in vacuo affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (910 mg, 88.5%) as a light yellow solid. mp: >250° C., MS: m/z=402.2/404.0 (M−H+)
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[NH:22][N:21]=2)[C:16]([Cl:31])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:31][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: FC(F)(F)COc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(OCC(F)(F)F)[nH]n2)n1)c1ncc(F)cn1
Temperature: 165 °C
Yield: 59.6 %

Procedure:
To a microwave vial was added (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 81 mg, 0.46 mmol), 2,5-dichloro-N-[5-(2,2,2-trifluoroethoxy)-1H-pyrazol-3-yl]pyrimidin-4-amine (Method 40, 100 mg, 0.31 mmol), and DIEA (110 mg, 0.9 mmol). Anhydrous n-BuOH (2.5 mL) was added, and the vial was heated in microwave oven at 165° C. for 5 hours. The reaction mixture was concentrated. The resulting residue was separated by silica gel column to afford desired product (80 mg, 62%). LC-MS, 433 (M+1). 1H NMR δ 12.19 (s, 1H), 9.76 (s, 1H), 8.83 (s, 2H), 7.92-8.10 (m, 2H), 5.67 (s, 1H), 5.13 (s, 1H), 4.75 (m, 2H), 1.49 (m, 3H).
Reaction SMILES: C1(C[NH:8][CH:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]2)C=CC=CC=1.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCCC(NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CCOC(=O)N1CCCC(N)CC1
Yield: 100 %

Procedure:
69.1 Parts of ethyl hexahydro-4-[(phenylmethyl)amino]-1H-azepine-1-carboxylate were hydrogenated in the prescence of a solution of thiophene in methanol at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 46.9 parts (100%) of ethyl 4-aminohexahydro-1H-azepine-1-carboxylate as a residue (interm. 28).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([CH3:25])[N:17]=1>C(OCC)(=O)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:21])=[C:18]([CH3:25])[N:17]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Stoichiometric amounts (0.04 mol) of methyl proplolate and ethyl 3-aminocrotonate were heated to 140° C. for 1 h. 1 g of the crude (2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMF was heated to 230° C. in a sealed microwave reactor for 40 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford crude ethyl 6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl 6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride was heated to 150° C. in a sealed microwave reactor for 15 min. The reaction mixture was poured into ice/water, extracted with diethyl ether. The combined organic layers were dried (MgSO4) and evaporated. Purified by silica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl 6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2-methylnicotinate was hydrolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid. 300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO4) and evaporated to afford 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide. Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 128 mg of 2,6-dimethylpiperazine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-methylnicotinamide. MS (Q1) 436.3 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[Li].[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.C[Mg]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH:15]([OH:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCC1CO1
Agent: C[Mg]I
Agent: [Li]C
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)cc2)CC(O)C1
Temperature: -78 °C

Procedure:
(4-Chlorophenyl)acetonitrile (1-1) (14.04 g) was dissolved in freshly distilled tetrahydrofuran (250 mL) and stirred at −78° C. under argon. Methyl lithium (LiBr complex, 1.5 M in diethyl ether, 62 mL, 1 eq) was added dropwise such that the reaction temperature stayed below −66° C. The solution was stirred for one h at −78° C. and turned from yellow to deep red. Epibromohydrin was added dropwise and the solution was stirred for an additional 90 min. Methylmagnesium iodide (3.0 M in diethyl ether, 31 mL) was added and the solution turned light brown as it was slowly warmed to room temperature and stirred overnight. The reaction was quenched with water (75 mL) and acidified to pH 2 with 5 N aqueous hydrochloric acid (ca. 30 mL). Brine was added until the layers separated. The organic layer was collected and the aqueous layer was reextracted with diethyl ether (2×50 mL). The organic layers were combined, dried with magnesium sulfate, filtered and concentrated to give crude 1-(4-chlorophenyl)-3-hydroxycyclobutane-1-carbonitrile (1-2).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.79 min; [M+H]+=420.50.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CCN(C(C)C)C(C)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[C:14]([O:13][C:11]([N:6]1[CH2:7][CH2:8][N:9]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:10][CH:5]1[C:3]([OH:2])=[O:4])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mmol of Piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester were dissolved in 20 ml methylenchloride. 1.05 eq of DIPEA and mesylchloride were added. The reaction mixture was stirred at room temperature for 30 min. The product was extracted from etylacetate/water. The crude material was redissolved in methanol and treated with 2N NaOH. The reaction mixture was stirred at room temperature for 2 h. The mixture was neutralized with HCl and the product isolated via extraction from ethylacetate/water.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13]Cl)[CH:11]=1>CS(C)=O.CCOC(C)=O>[Br:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13][NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1
Reactant: ClCCn1cc(Br)cn1
Reactant: COCCN
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCNCCn1cc(Br)cn1
Temperature: 25 °C

Procedure:
A solution of 2-methoxyethanamine (8.9 mL, 102.06 mmol) and chloride 75 (7.13 g, 34.02 mmol) in DMSO (20 mL) was heated at 60° C. 5 h. The mixture was then cooled to room temperature, diluted with EtOAc, washed with aqueous sodium bicarbonate, water and brine.
Reaction SMILES: [CH3:1][CH:2]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH:5]([CH3:9])[CH:6]([CH3:8])[CH3:7].[CH2:20](Br)[C:21]#[CH:22]>>[CH2:22]([O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:11]([O:10][CH:2]([CH3:1])[CH2:3][CH2:4][CH:5]([CH3:9])[CH:6]([CH3:7])[CH3:8])=[CH:12][CH:13]=1)[C:21]#[CH:20]
Reactant: C#CCBr
Reactant: CC(CCC(C)C(C)C)Oc1ccc(C(=O)O)cc1
Product: C#CCOC(=O)c1ccc(OC(C)CCC(C)C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,4,5-trimethylhexyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(1,4,5-trimethylhexyl)oxy]benzoic acid propargyl ester; nD22 = 1.5050.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH2:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2)[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1Cc1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1Cc1ccccc1
Temperature: 90 °C
Yield: 30.1 %

Procedure:
A mixture of (S)-1-(1-benzyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (322 mg, 1.20 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (286 mg, 1.20 mmol) and DIPEA (1.07 mL, 5.98 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial overnight. The resultant mixture was allowed to cool to RT and then concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH solution to afford a pale red gum. This was purified by column chromatography (silica gel, gradient 0-10% [2M NH3 in MeOH] in DCM) to afford 393 as a white solid (140 mg, 31%). LCMS (Method K): RT 3.21 min [M+H]+ 388.1 1H NMR (DMSO-d6, 400 MHz): δ 8.20 (1H, s), 8.13 (1H, s), 8.04-7.93 (1H, s), 7.63 (1H, dd, J=8.80, 4.92 Hz), 7.35-7.17 (4H, m), 7.16-7.10 (2H, m), 7.03 (1H, ddd, J=9.91, 8.78, 2.52 Hz), 5.93-5.75 (1H, m), 5.61 (2H, s), 1.59 (3H, d, J=6.77 Hz)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[N:29][NH:30]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Temperature: 45 °C
Yield: 60.9 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 3.2 mmol) in n-butyl alcohol (12 mL) was added 6-aminoindazole (0.47 g, 3.52 mol) and DIPEA (0.86 mL, 4.80 mmol). After heating at 45° C. for 15 h, the mixture was cooled to room temperature, and the resulting precipitates were collected by filtration to give 2-chloro-N-(1H-indazol-6-yl)-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.1 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][N:9]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(CC)CC)C>ClCCl>[CH3:14][O:13][C@H:11]1[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:8]([CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12]1
Reactant: CO[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.175 mL, 2.26 mmol, 1.2 equiv) was added to a solution of (2S,4R)-2-(hydroxymethyl)-4-methoxy-1-pyrrolidinecarboxylate (3-3, 0.500 g, 1.88 mmol, 1 equiv) and triethylamine (0.394 mL, 2.83 mmol, 1.50 equiv) in dichloromethane (30 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 1 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution and dichloromethane (2×40 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane initially, grading to 100% EtOAc) to provide benzyl (2S,4R)-4-methoxy-2-{[(methylsulfonyloxy]methyl}-1-pyrrolidinecarboxylate (3-4) as a light yellow oil. 1H NMR (300 MHz, CDCl3) major rotamer: δ7.37-7.25 (br m, 5H), 5.17 (d, 1H, J=11.8 Hz), 5.10 (d, 1H, J=11.8 Hz), 4.65 (dd, 1H, J=8.3, 3.8 Hz), 4.24 (br m, 2H), 3.95 (m, 1H), 3.68 (br d, 1H, J=12.0 Hz), 3.45 (dd, 1H, J=12.0, 4.4 Hz), 3.30 (s, 3H), 2.88 (s, 3H), 2.39 (m, 1H), 2.12 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:3]=1[O:4][C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:25][N:26]=[C:27]=[O:28]>C1C=CC=CC=1>[CH3:25][NH:26][C:27]([N:8]1[CH2:7][CH2:6][C:5]([O:4][C:3]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:2]=2[F:1])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)=[O:28]
Reactant: Fc1c(F)c(F)c(OC2(c3ccccc3)CCNCC2)c(F)c1F
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
A solution of 5.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine in 50 ml of benzene was treated with a solution of 0.9 g of methyl isocyanate in 20 ml of benzene over a period of ten minutes. The reaction mixture was then stirred at ambient temperature for two hours. Evaporate of the volatiles afforded a solid which was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane) to yield 4.0 g (69%) of 1-(N-methylamino)carbonyl-4-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpiperidine, m.p. 87°-89° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][C@H:31]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[C:32]([O:34][CH3:35])=[O:33])(=[O:28])=[O:27])=[CH:22][CH:21]=1>CC(C)=O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH2:30][C@H:31]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[C:32]([O:34][CH3:35])=[O:33])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCCCC1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccc3ccccc3c2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
420 mg (1.3 mmol) of cesium carbonate, followed by 280 mg (1.3 mmol) of 2-bromomethylnaphthalene, are added to a solution of 400 mg (1.2 mmol) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-piperidin-1-ylpropanoate (prepared as described in 3.1) in 10 ml of acetone. The reaction medium is stirred at ambient temperature for 18 h and then filtered. The filtrate is concentrated under vacuum and purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 420 mg (80%) of methyl(S)-3-[4-(naphthalen-2-ylmethoxy)benzenesulfonylamino]-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)=[C:15]([F:26])[CH:14]=1>>[F:26][C:15]1[CH:14]=[C:13]([C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:18]=[CH:17][C:16]=1[C:19]1[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1
Reactant: COc1ncccc1B(O)O
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: COc1ncccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using (2-(methoxy)pyridin-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C16H13FN4O, 296.11; m/z found, 297.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.62-8.56 (m, 1H), 8.19 (dd, J=1.9, 5.0, 1H), 8.12 (d, J=1.5, 1H), 8.01-7.94 (m, 1H), 7.70-7.65 (m, 1H), 7.48-7.41 (m, 2H), 7.00 (dd, J=5.0, 7.31, 1H), 4.66 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:30]=1[CH3:47]>CCOC(C)=O>[Cl:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:30]([CH3:47])[C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])=[N:32]2)=[CH:37][CH:36]=1
Reactant: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2F)nc2cc(Cl)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a N2 atmosphere, 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.18 g, 0.65 mmol) was dissolved in DMF (2.00 mL, 26 mmol) and sodium hydride (0.017 g, 0.72 mmol) was added. The reaction was allowed to stir for 15 minutes at rt. 4,7-Dichloro-2-(2-fluorophenyl)-3-methylquinoline (0.100 g, 0.33 mmol) was added and the reaction was heated to 140° C. for 5 h. The reaction was diluted with EtOAc and washed with 2% sodium bicarbonate then brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude solid was purified by flash column chromatography eluting with 40% to 60% EtOAc in hexane, followed by further purification by preparative reverse phase HPLC to afford 1-(7-chloro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. Mass Spectrum (ESI) m/e=544.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (1H, d, J=2.3 Hz), 7.90 (1H, d, J=9.0 Hz), 7.54-7.65 (3H, m), 7.35-7.42 (2H, m), 7.11 (1H, d, J=8.2 Hz), 6.30 (1H, dd, J=8.2, 2.3 Hz), 5.57 (1H, d, J=2.3 Hz), 4.06 (1H, d, J=9.4 Hz), 3.80-3.92 (3H, m), 3.56-3.63 (4H, m), 3.40-3.54 (2H, m), 2.83-2.89 (4H, m), 2.06 (3H, d, J=1.6 Hz), 1.88-2.03 (2H, m), 1.81-1.87 (1H, m), 1.66 (1H, dt, J=13.4, 1.1 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(-c3ccccc3)n2)c1
Temperature: 80 °C

Procedure:
{3-[(6-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (77) (198 mg, 0.54 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. for 25 min. The crude product was purified by column chromatography using 20% EtOAc in heptane to give the title compound.