Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.[OH-].[K+].CS(C)=O>C(O)C>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 71 %

Procedure:
0.728 g (2 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 0.730 g (13 mmole) of KOH in solution in 10 ml of ethyl alcohol were heated to reflux for 1 hour. After addition of 2 ml of DMSO, the reaction mixture was heated to 120° and the excess of ethyl alcohol distilled therefrom. The resulting mixture was then heated at 110° for 12 hours, then treated as indicated hereinabove to afford 0.29 g (71% yield) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5].[CH2:16]([NH2:21])[CH2:17]CCC.[C:22]12[C:28](=CC=CC=1)[NH:27]C(=O)OC2=O>>[NH:27]1[CH2:28][CH2:22][N:21]=[C:16]1[CH2:17][NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:5]
Reactant: CCCCCNC(=O)c1ccccc1N
Reactant: CCCCCN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: CCCCCNC(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-pentylbenzamide (prepared from amylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N-pentylbenzamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:10]=32)[C:6](=[O:19])[NH:5][CH2:4][CH2:3]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:54][CH:55]([N:57]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:59]=[C:58]1[NH2:66])[CH3:56].Br.C(N(CC)CC)C>CN(C=O)C>[CH3:20][C:2]1([CH3:1])[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([NH:66][C:58]4[N:57]([CH:55]([CH3:56])[CH3:54])[C:61]5[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=5[N:59]=4)=[O:18])=[CH:12][C:10]=32)[C:6](=[O:19])[NH:5][CH2:4][CH2:3]1
Reactant: CC(C)n1c(N)nc2ccccc21
Reactant: CC1(C)CCNC(=O)c2nc3ccc(C(=O)O)cc3n21
Agent: Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1c(NC(=O)c2ccc3nc4n(c3c2)C(C)(C)CCNC4=O)nc2ccccc21
Reaction time: 16 h
Yield: 50 %

Procedure:
A solution of 5,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylic acid (Intermediate C, 45 mg, 0.16 mmol) and PyBOP (145 mg, 0.28 mmol) in DMF (1.5 mL) is stirred for 10 min. 1-(Propan-2-yl)-1H-benzimidazol-2-amine; hydrobromide (Intermediate M, 71 mg, 0.28 mmol) and triethylamine (0.08 mL, 0.56 mmol) are added and the reaction is stirred for 16 h. The mixture is purified via preparative HPLC to afford the title compound (35 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N+:7]([O-:31])[CH:6]=[CH:5]3)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ccc2cnccc2c1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1ccc2c[n+]([O-])ccc2c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
The compound obtained using 6-aminoisoquinoline (0.5 g, Synthesis, 733 (1975)) and 4-chlorobenzenesulfonyl chloride (0.88 g) in the same method as in Synthetic Example 1b was dissolved in chloroform (150 ml). Under ice-cooling, m-chloroperbenzoic acid (0.9 g) was added thereto, followed by stirring at room temperature overnight. The solvent was evaporated, and the resulting crystals were washed with diethyl ether, collected by filtration and dried, to give 6-(4-chlorobenzenesulfonylamino) isoquinoline-N-oxide (1.072 g) In acetonitrile (1.5 ml) was dissolved 50 mg in the amount of the product, to which were then added trimethyl cyanide (0.08 ml) and triethylamine (0.04 ml), followed by heating under reflux for 3.5 hours. After evaporating the solvent, the residue was purified by silica gel column, to give the title compound (23 mg, 64%) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14]([OH:16])=[O:15]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C@@H:13]([CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(F)cc1

Procedure:
In a manner to Example 4(a), 4-fluoro-benzene-sulfonyl chloride was condensed with (S)-2-amino-3-(1H-Indol-3-yl)-propionic acid to give the title compound, mp=57-60° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:34])[CH:20]([CH:21]=[C:22]([Br:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:19]1[C:31](Cl)=[O:32].[C-:35]#[N:36].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCC>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]([O:12][C:31]([CH:19]1[CH:20]([CH:21]=[C:22]([Br:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:18]1([CH3:34])[CH3:17])=[O:32])[C:35]#[N:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(C=C(Br)c2ccc(Cl)cc2)C1C(=O)Cl
Reactant: [C-]#N
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C(C=C(Br)c2ccc(Cl)cc2)C1C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Yield: 70.3 %

Procedure:
4.32 g (0.02 mol) of 3-phenoxy-4-fluoro-benzaldehyde and 6.96 g (0.02 mol) of 2,2-dimethyl-3-(2-bromo-2-(4-chlorophenyl)-vinyl)-cyclopropanecarboxylic acid chloride were together added dropwise to a mixture of 1.6 g of sodium cyanide, 2.5 ml of water, 100 ml of n-hexane and 0.5 g of tetrabutylammonium bromide at 20°-25° C., while stirring, and the mixture was then stirred at 20°-25° C. for 4 hours. 300 ml of toluene were then added to the reaction mixture and the mixture was extracted by shaking twice with 300 ml of water each time. The organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 7.8 g (70.3% of theory) of 2,2-dimethyl-3-(2-bromo-2-(4-chloro-phenyl)-vinyl)-cyclopropanecarboxylic acid 3-phenoxy-4-fluoro-α-cyano-benzyl ester were obtained as a viscous oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11]([O:13][CH2:14][CH2:15]Br)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:13][CH2:14][CH2:15][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:12]
Reactant: CCOCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCCOc1ccccc1[N+](=O)[O-]
Yield: 42.2 %

Procedure:
2-Nitrophenol (91.0 g., 0.65 mole), 2-bromoethyl ethyl ether (100.0 g., 0.65 mole), anhydrous potassium carbonate (9.0 g, 0.72 mole) and acetone (1 liter) were refluxed for 65 hours. The reaction mixture was filtered, and the acetone removed by rotary evaporation. The residue was partitioned between 200 ml. of dichloromethane and 100 ml. water. The organic phase was further washed with 200 ml. of 10% sodium hydroxide followed by 100 cc of water. The product (58.0 g) was obtained in 42% yield by a vacuum distillation (100°-120° C./0.5 mm).
Reaction SMILES: Cl[CH:2]([Cl:4])C.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[O:15]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:15][CH2:2][Cl:4])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(Cl)Cl
Reactant: C1COOOC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: O=C(OCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 10 ml of dichloroethane were added 1.32 g of zirconium tetrachloride and 1 g of 4-fluorobenzoyl chloride, and the mixture was stirred at room temperature for 20 minutes. The mixture was cooled to 0° C., 0.21 g of trioxane was added, and the mixture was stirred for 1 hour, and further stirred at room temperature for 1 hour. Water was added slowly at 0° C., the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to obtain 0.89 g of chloromethyl 4-fluorobenzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:11]3[C:10]([I:25])=[N:9]2)=[CH:4][CH:3]=1.C=O.[BH3-][C:29]#N.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[I:25][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:29])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc(N)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1ccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a solution of tert-butyl 1-(4-aminophenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (29) (500 mg, 1.11 mmol) in THF (15 mL) was added HCHO solution (135 mg, 1.66 mmol, 37% solution in water) under N2. The reaction was warmed to 30° C. for 4 h and then NaBH3CN (70 mg, 1.11 mmol) was added. The reaction mixture was stirred for 1 h at 30° C. followed by the addition of NaBH(OAc)3 (235 mg, 1.11 mmol). The reaction mixture was stirred overnight at 30° C. The reaction mixture was quenched with sat. aqueous NaHCO3 and extracted with 85% DCM/IPA (15 mL×3). The organic solution was dried and concentrated. The residue was purified by flash chromatography to provide tert-butyl 3-iodo-1-(4-(methylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (30) (170 mg, 33%) as a yellow solid. LC-MS (ESI): m/z (M+1) 467.0.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][CH:14]=1)([O-])=O.[Cl-].[NH4+:29].C(O)C>O>[NH2:29][C:25]1[CH:26]=[CH:27][CH:4]=[CH:5][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1occc1-c1cccc(OCc2cccc([N+](=O)[O-])c2)c1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1occc1-c1cccc(OCc2ccccc2N)c1
Yield: 78.8 %

Procedure:
A mixture of ethyl 3-[3-(3-nitrobenzyloxy)phenyl]-2-furancarboxylate (2.21 g), reduced iron (1.75 g), ammonium chloride (0.67 g), ethanol (30 ml) and water (10 ml) was heated at reflux for 1 hour. After filtering the reaction solution through celite, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/3), thereby giving 1.60 g of ethyl 3-[3-(2-aminobenzyloxy)phenyl)-2-furancarboxylate.
Reaction SMILES: [OH-].[Na+].O1CCC[CH2:4]1.COC1C=C(C=CC=1OC[C:39]1N=[C:41]([C:45]2C=CC=CC=2)[O:42][C:43]=1[CH3:44])CN1C2C=CC=C(O[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])C=2C2C1=CC=CC=2.Cl>O.CO>[C:29]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:28].[CH:41]([O:42][CH:43]([CH3:39])[CH3:44])([CH3:45])[CH3:4]
Reactant: CCOC(=O)COc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)OC(C)C
Product: CCOC(C)=O

Procedure:
1 mL of 5 N sodium hydroxide solution was added to tetrahydrofuran:methanol=1:1 (10 mL) solution of 107 mg of ethyl 2-{9-[3-methoxy-4-((5-methyl-2-phenyl-oxazole-4-yl)methoxy)-benzyl]-9H-carbazole-4-yloxy}acetate, and stirred at room temperature for 1 hour. The reaction mixture was diluted with water, adjusted to pH3 by 1 N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The crystals of residue were isolated by filtration with ethyl acetate-diisopropylether, dried under reduced pressure, and 74 mg of the subject compound was prepared as pale yellow crystal.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:11][C:10]([F:13])([F:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:29]2[CH2:30][CH2:31][CH:27]([O:26][C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:33][CH:32]=3)[CH2:28]2)=[CH:4][CH:5]=1)([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(OC2CCNC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C2)cc1
Yield: 16.8 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (9.61 mmol, 4.63 mL, 3.24 g), 3-(4-nitrophenoxy)pyrrolidine (9.61 mmol, 2 g) and potassium carbonate (19.21 mmol, 2.65 g) were combined and stirred at room temperature in acetonitrile (50 mL) for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica column chromatography (eluent: dichloromethane to 15% methanol in dichloromethane) and SCX chromatography to afford the intermediate 1,1,1,3,3,3-hexafluoro-2-(4-((3-(4-nitrophenoxy)pyrrolidin-1-yl)methyl)phenyl)propan-2-ol (750 mg).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5].[CH2:22]([O:24]C(OCC)OCC)[CH3:23].C(O)CO>C1(C)C=CC=CC=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH3:1][O:2][N:3]([CH3:21])[C:4]([C@H:6]1[CH2:7][CH2:8][C@@H:9]([C:12]2([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[O:24][CH2:22][CH2:23][O:20]2)[CH2:10][CH2:11]1)=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](C(=O)c2ccc(Cl)cc2)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: OCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CON(C)C(=O)[C@H]1CC[C@@H](C2(c3ccc(Cl)cc3)OCCO2)CC1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of cis-4-(4-chlorobenzoyl)-cyclohexanecarboxylic acid, methoxy-methyl amide (1.6 g, 5.17 mmol), triethylorthoformate (843 mg, 0.95 mL, 5.7 mmol), ethylene glycol (1.6 g, 1.45 mL, 25.9 mmol) and toluenesulfonic acid monohydrate (50 mg) in toluene (50 mL) was stirred overnight at 60° C., and then cooled to room temperature and concentrated to dryness in vacuo. The reaction mixture was redissolved in ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-30% ethyl acetate in heptane) gave cis-4-[2-(4-chlorophenyl)-[1,3]-dioxolan-2-yl]-cyclohexanecarboxylic acid, methoxy-methyl amide as a colorless oil (1.36 g, 74%); 1H NMR (CDCl3, 300 MHz) δ 7.33 (d, J=8.5 Hz,), 7.27 (d, J=8.5 Hz, 2H), 3.96 (m, 2H), 3.68 (m, 2H), 3.64 (s, 3H), 3.14 (s, 3H), 2.83 (m, 1H), 1.96 (m, 2H), 1.76 (m, 1H), 1.67 (m, 3H) and 1.47 (m, 4H); MS (+CI): m/z for C18H24ClNO4: expected 353.1. found 354.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:6]=1.[NH2:25][C@@H:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][NH:25][C@@H:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)[CH:6]=1
Reactant: N[C@H]1CCc2ccccc21
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and (S)-(+)-1-aminoindan.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:15]([F:17])[F:16])[N:6]=1.[O:30]1[C:34]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1>CC(N(C)C)=O>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH:15]([F:17])[F:16])=[C:7]([C:5]2[N:6]=[C:2]([N:37]3[CH2:38][CH2:39][C:34]4([O:33][CH2:32][CH2:31][O:30]4)[CH2:35][CH2:36]3)[S:3][C:4]=2[NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[CH:12]=1
Reactant: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: C1CC2(CCN1)OCCO2
Solvent: CC(=O)N(C)C
Product: O=C(Nc1sc(N2CCC3(CC2)OCCO3)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 165 °C
Yield: 58.6 %

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (820 mg, 1.64 mmol) and 1,4 dioxa-8-azaspiro[4.5]decane (1.05 ml, 8.2 mmol) were dissolved in DMA (10 ml) and heated in a microwave at 165° C. for 1 hour. The reaction mixture partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with brine. The combined aqueous layers were extracted with ethyl acetate once and the organic layers combined, dried (Na2SO4), filtered and the solvent removed. The crude product was chromatographed on silica eluting with 50-60% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-(5-chloro-2-difluoromethoxy-phenyl)-2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-thiazol-5-yl]-amide as a yellow solid (541 mg, 59%). LCMS (Method 3) [M+H]+=563.3, RT=3.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.26 (s, 1H), 9.37 (dd, 1H, J=1.6, 6.9 Hz), 8.69 (s, 1H), 8.64 (dd, 1H, J=1.5, 4.4 Hz), 7.68 (d, 1H, J=2.5 Hz), 7.59 (dd, 1H, J=2.7, 8.7 Hz), 7.42 (d, 1H, J=8.5 Hz), 7.31 (dd, 1H, J=4.3, 7.0 Hz), 7.18 (t, 1H, J=73.8 Hz), 3.94 (s, 4H), 3.52 (dd, 4H, J=5.7, 5.7 Hz), 1.75 (dd, 4H, J=5.7, 5.7 Hz).
Reaction SMILES: [C:1](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:4])[CH:2]=[CH2:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:22]([NH2:32])=[CH:21][C:20]=1[NH:33][C:34]1[N:39]=[C:38]([C:40]2[CH:41]=[N:42][N:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=23)[CH:37]=[CH:36][N:35]=1>CN(C=O)C.C(Cl)Cl>[CH3:17][O:18][C:19]1[C:20]([NH:33][C:34]2[N:39]=[C:38]([C:40]3[CH:41]=[N:42][N:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=34)[CH:37]=[CH:36][N:35]=2)=[CH:21][C:22]([NH:32][C:1](=[O:4])[CH:2]=[CH2:3])=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[CH:24]=1
Reactant: C=CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.7 %

Procedure:
(2,3,4,5,6-Pentafluorophenyl) prop-2-enoate (0.030 mL, 0.19 mmol) was added dropwise to a solution of 4-methoxy-6-(4-methylpiperazin-1-yl)-N′(4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 69, 67 mg, 0.16 mmol) in DMF (0.6 mL) at r.t. under N2. The resulting solution was stirred at r.t. for 1.5 h and then diluted with CH2Cl2 (9 mL). This solution was added to 1.5 g flash silica which was wet with CH2Cl2 in a dry-loaded cartridge, and the crude product was eluted from the silica using CH2Cl2. Further purification by FCC, eluting with 2-7% of 2N methanolic ammonia in CH2Cl2 provided material which was further purified by FCC, eluting with 5-20% CH3OH in CH2Cl2. Appropriate fractions were concentrated in vacuo and trituration provided a crystalline solid that was washed with THF (0.1 mL) to give the title compound (23 mg, 28%) as a beige crystalline solid; 1H NMR: 2.33-2.43 (3H, m), 2.62-2.81 (4H, m), 2.94 (4H, s), 3.85 (3H, s), 5.72 (1H, d), 6.18 (1H, m), 6.55-6.69 (1H, m), 6.89 (1H, s), 7.05 (1H, m), 7.26 (1H, d), 7.35-7.43 (1H, m), 8.15 (1H, s), 8.34 (1H, d), 8.44 (1H, d), 8.49 (1H, s), 8.79 (1H, d), 8.80 (1H, s), 9.03 (1H, s); m/z: ES+ MH+ 485.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[N:8]=2)[CH2:3]1.N1([C:30]([O:32][CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[O:31])C=CN=C1.C(N(CC)CC)C>C(Cl)Cl>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:30](=[O:31])[O:32][CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(OCC1CCCCO1)n1ccnc1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC4CCCCO4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (100 mg, 0.31 mmol) and (tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate (98 mg, 0.47 mmol) was added 1.04 mL CH2Cl2 and triethylamine (65 μL, 47 mg, 0.46 mmol). The mixture was stirred at room temperature overnight. An additional equivalent of (tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate (100 mg, 0.47 mmol) was added to the mixture, and the reaction was heated at 45° C. for 4 hours. Purification via silica gel chromatography using 10%-100% ethyl acetate/hexanes gave (tetrahydro-2H-pyran-2-yl)methyl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 463.4 (M+H)+ at 2.66 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14])([O-:10])=[O:9].[C:20]1([CH:26]2[NH:31][C:30](=[O:32])[CH2:29][C:28](=O)[CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([C:28]1[CH2:27][CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:31][C:30](=[O:32])[CH:29]=1)=[O:14])([O-:10])=[O:9]
Reactant: O=C1CC(=O)NC(c2ccccc2)C1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C=C(C(=O)c2ccccc2[N+](=O)[O-])CC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.4 %

Procedure:
Triethylamine (3.4 ml) was added at 0°-5° C. to a stirred solution of 2-nitrobenzoyl chloride (4.9 g) and 6-phenylpiperidine-2,4-dione (5 g) in dry dichloromethane (100 ml) and the mixture stirred at ambient temperature for 3.5 hours. The solution was washed successively with 2N hydrochloric acid (25 ml), water (2×25 ml), 5% w/v aqueous sodium carbonate solution (25 ml) and water (3×25 ), dried over magnesium sulphate and evaporated under reduced pressure to give a pale yellow solid which was recrystallised from a mixture of ethyl acetate and hexane (4:1; 20 ml) to give 5,6-dihydro-4-(2-nitrobenzoyl)-6-phenylpyridin-2(1H)-one (4.8 g), mp 139°-141° C., as a light yellow crystalline solid.