Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[C:8]([Cl:19])[CH:7]=1)[CH3:5].[OH-].[K+].Cl>CO>[Cl:19][C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:20])=[O:2])[CH:11]=[CH:10][C:9]=1[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]
Reactant: COC(=O)C(C)c1ccc(CC2CCCC2=O)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc(CC2CCCC2=O)c(Cl)c1
Yield: 88.2 %

Procedure:
5 g of methyl-2-[3-chloro-4-(2-oxocyclopentane-1-yl methyl)phenyl]propionate were incorporated with 80 ml of an aqueous methanol containing 2.9 g of potassium hydroxide and then refluxed under heat for two hours. After the completion of the reaction, the reaction mixture obtained was treated to concentrate the solvent at a reduced pressure, incorporated with 50 ml of water, washed with 50 ml of ethyl acetate, after which the aqueous layer obtained was adjusted to a pH of 2 with conc. hydrochloric acid, thereafter extracted with 60 ml of ether, washed with water, dried and then freed of the solvent to obtain a residue. The thus obtained residue was distilled at a reduced pressure thereby to obtain 4.2 g (yield 88%) of oily 2-[3-chloro-4-(2-oxocyclopentane-1-yl methyl)phenyl]propionic acid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:12]3[CH2:13][N:8]([C:9]4[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:10]=4[CH2:11]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[CH:12]3[CH2:13][N:8]([C:9]4[CH:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:10]=4[CH2:11]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)N1CCN(CC3CC3)C(C2)C1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)N1CCN(CC3CC3)C(C2)C1
Reaction time: 2 h

Procedure:
A mixture of 4-cyclopropylmethyl-9-amino-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (3 g.), acetic anhydride (10 ml.) and pyridine (25 ml.) was let stand for two hours at room temperature, then concentrated to dryness. The residue was partitioned between aqueous ammonia and chloroform. The chloroform layer was dried and concentrated to dryness. Recrystallization of the residue from ether afforded 4-cyclopropylmethyl-9-acetamido-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (2.5 g., m.r. 131°-132° C.), the compound of Formula V wherein Q is cyclopropylmethyl and R"CONH is acetamido.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH2:24][CH:23]4[N:25](C(OC(C)(C)C)=O)[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:16])[CH2:11]2)=[N:7][CH:8]=1)#[N:2].[ClH:33].O1CCOCC1>C(Cl)Cl>[ClH:33].[ClH:33].[CH:20]12[NH:25][CH:23]([CH2:22][CH2:21]1)[CH2:24][CH:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][C@@H:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH2:11]1)=[O:16])[CH2:19]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(NC(=O)N1CC[C@@H](Nc3ccc(C#N)cn3)C1)C2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(N[C@@H]2CCN(C(=O)NC3CC4CCC(C3)N4)C2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl 3-((R)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (49 mg, 0.11 mmol) was dissolved in CH2Cl2 (2.5 mL) and 4 M HCl in dioxane (0.8 mL, 3.2 mmol) was added. The mixture was stirred at rt for 1 h and concentrated to give (3R)—N-(8-azabicyclo[3.2.1]octan-3-yl)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamide dihydrochloride (46 mg, quant).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1>>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5C)n4c3)c3ccccc32)cc1

Procedure:
The title compound was prepared with Intermediate 5c and [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety) using an analogous procedure to that described in Example 1 step d. LCMS (Method 5): Rt 3.76 min, m/z 319 [MH+]. 1H NMR (400 MHz, CDCl3): 1.33 (9H, s), 1.88-2.12 (6H, m), 2.21 (3H, s), 2.21-2.30 (2H, m), 2.33-2.39 (1H, m), 2.37 (3H, s), 3.19-3.24 (1H, m), 3.98-4.02 (1H, m), 5.05-5.12 (1H, m), 5.17 (1H, t, J 4.0), 5.25 (1H, d, J 8.7), 6.25-6.27 (2H, m), 7.03 (1H, dd, J 2.0, 9.8), 7.22-7.34 (6H, m), 7.40 (2H, d, J 8.5), 7.61 (1H, d, J 9.8), 8.27 (1H, m).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[C:20]([N+:36]([O-:38])=[O:37])=[CH:19][N:18]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][NH:16][C:17]1[N:22]=[C:21]([NH:23][CH2:24][C@H:25]2[CH2:26][CH2:27][C@H:28]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:29][CH2:30]2)[C:20]([N+:36]([O-:38])=[O:37])=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNc2ncc([N+](=O)[O-])c(NCC3CCC(N4CCCC4)CC3)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(CNc2ncc([N+](=O)[O-])c(NC[C@H]3CC[C@H](N4CCCC4)CC3)n2)c1

Procedure:
To a solution of [3-({5-nitro-4-[(4-pyrrolidin-1-yl-cyclohexylmethyl)-amino]-pyrimidin-2-ylamino}-methyl)-benzyl]-carbamic acid tert-butyl ester (132 mg, 0.25 mmol) in DCM (1 mL) was added TFA (2 mL). After 20 min the reaction mixture was concentrated in vacuo and the resulting oil taken up in EtOAc and the solution washed with sat. NaHCO3. The aqueous layer was then extracted with 90:10 CHCl3/i-PrOH. The combined organic layers were concentrated in vacuo and the residue purified by column chromatography (silica gel, 96:4 to 93:7 DCM/10% NH4OH in MeOH) to afford the title compound (25 mg), m/z 440 (M+1)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[CH:45]=[CH:44][C:38]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[C:37]([I:46])[CH:36]=1.[CH2:47]=[C:48]([CH2:51][CH2:52][OH:53])[CH2:49]O>O1CCCC1>[Cl:34][C:35]1[CH:45]=[CH:44][C:38]([N:39]([CH2:49][C:48](=[CH2:47])[CH2:51][CH2:52][OH:53])[S:40]([CH3:43])(=[O:42])=[O:41])=[C:37]([I:46])[CH:36]=1
Reactant: CS(=O)(=O)Nc1ccc(Cl)cc1I
Reactant: C=C(CO)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(CCO)CN(c1ccc(Cl)cc1I)S(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
To a stirred solution of triphenylphosphine (2.75 g) in tetrahydrofuran (60 ml) at −10° C. under argon was added dropwise diisopropylazodicarboxylate (DIAD, 2.1 ml); the resulting suspension was stirred at −10° C. for 15 min then 4-chloro-2-iodo-N-methanesulfonyl-aniline (3.1 g) was added as a solid followed by 2-methylene-butane-1,4-diol (0.95 g) dissolved in a minimum of tetrahydrofuran. The reaction mixture was stirred at room temperature for 6 hours, the solvent was evaporated in vacuo and the residue was purified by silica gel chromatography (eluent ethyl acetate:cyclohexane 4:6) to afford N-(4-Chloro-2-iodo-phenyl)-N-(4-hydroxy-2-methylene-butyl)-methanesulfonamide (3.5 g) contaminated with triphenylphosphine oxide.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2nnc3ccc(F)cn23)CC1
Yield: 32.3 %

Procedure:
A solution of Intermediate 24b (451 mg, 2.50 mmol) and N-methyl-piperazine (1.11 mL, 10.0 mmol) in DMA (10 mL) was heated in the microwave at 170° C. for 8 h. The mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM, to give the title compound as an orange gum (190 mg, 32%). LCMS (Method 3): Rt 0.43 min, m/z 236 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[NH:10][C@@H:9]2[C:14]2[C:15]([O:28][CH3:29])=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=2)[CH:5]=[CH:6][CH:7]=1.[F:30]C1C=CC(F)=CC=1[C@H]1OC(=O)N[C@@H]1C1C(F)=NC=C(C#CC2C=CC=CC=2)C=1>>[F:30][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C@H:8]1[O:12][C:11](=[O:13])[NH:10][C@@H:9]1[C:14]1[C:15]([O:28][CH3:29])=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=1
Reactant: COc1ncc(C#Cc2ccccc2)cc1[C@H]1NC(=O)O[C@@H]1c1cccc(F)c1
Reactant: O=C1N[C@H](c2cc(C#Cc3ccccc3)cnc2F)[C@@H](c2cc(F)ccc2F)O1
Product: COc1ncc(C#Cc2ccccc2)cc1[C@H]1NC(=O)O[C@@H]1c1cc(F)ccc1F

Procedure:
Prepared according to the same procedure as (4R,5R)-5-(3-fluorophenyl)-4-(2-methoxy-5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one, starting with ((4R,5R)-5-(2,5-difluorophenyl)-4-(2-fluoro-5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one. 1H NMR (CDCl3) δ: 8.33 (d, J=2.1 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.50-7.54 (m, 2H), 7.33-7.38 (m, 3H), 7.20-7.25 (m, 1H), 7.03-7.10 (m, 2H), 6.06 (s, 1H), 5.54 (d, J=5.2 Hz, 1H), 4.98 (d, J=5.2 Hz, 1H), 3.88 (s, 3H). 19F NMR (CDCl3) δ: −119.97-115.26 (m, 1F), −123.84 (br. s., 1F). Mass spec.: 407.1 (MH)+.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7](O)=O)=[N:4][N:3]=[N:2]1.[NH2:10][C:11]1[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:16]=1[NH2:17]>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[C:16]3[N:17]=[C:7]([CH2:6][C:5]4[NH:1][N:2]=[N:3][N:4]=4)[NH:10][C:11]=3[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14]2=[O:29])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=C(O)Cc1nnn[nH]1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3nnn[nH]3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 1H-tetrazole-5-acetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine. By the method of Example 3, this substance is alkylated with a mixture of 1,2-dichloroethane, sodium carbonate, and ethylamine to yield 7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine. By the method of Example 4,7-(2-ethylamino)ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-7-(2-ethylamino)ethyl-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine free base. The corresponding hydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C@@H:3]([OH:31])[C:4]([N:6]1[CH2:30][CH2:29][CH2:28][C@H:7]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:9])=[O:5].Cl>C(Cl)Cl.CCOCC>[CH3:1][C:2]([CH3:33])([CH3:32])[C@@H:3]([OH:31])[C:4]([N:6]1[CH2:30][CH2:29][CH2:28][C@H:7]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][NH2:20])=[O:9])=[O:5]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](O)C(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[C@@H](O)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN
Temperature: 0 °C
Reaction time: 20 h

Procedure:
1-((2R)-3,3-Dimethyl-2-hydroxybutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide from the previous step (4.65 g, 9.65 mmol, HPLC RT=3.35 min) was dissolved in CH2Cl2 (15 mL) and cooled with stirring to 0° C. A solution of anhydrous HCl in ether (38 mL of a 1 Molar solution, 38 mmol) was added slowly. The resulting solution was stirred at 0° C. for 10 min, and then at ambient temperature for 20 h. The solid which had formed was collected by filtration and washed with several portions of ether. The solid was purified by preparative reverse-phase HPLC using an acetonitrile:water gradient containing 0.05% concentrated HCl. The product-containing fractions were combined and lyophilized to give the hydrochloride salt of the title compound as a white solid (HPLC RT=2.52 min, method A; LC-MS m/z=382; C, H, N combustion analysis, calculated for C19H28ClN3O3, 1.0HCl, 1.5H2O, calculated C, 51.24, H, 7.24, N, 9.43, found C, 51.32, H, 7.17, B, 9.33).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:30][CH2:29][C:28]([O:32][CH3:33])=[O:31])=[O:15])[CH3:14]
Reactant: C=CC(=O)OC
Reactant: CCOP([O-])CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCCCc1ccccc1)CCC(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (15 ml) was added triethylamine (0.34 ml, 0.0024 mole), trimethyl silylchloride (0.31 ml, 0.0024 mole) and methyl acrylate (0.22 ml, 0.0024 mole). The reaction mixture was stirred at room temperature for 4 hours and then stirred at reflux for 23 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 5% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water and 5% NaHCO3, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a clear liquid solid (0.6 g). The crude product was purified through column chromatography (1:1 hexane/acetone eluting solvent system) to yield 0.19 g oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH3:21])=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH3:21])=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: O=CNc1ccc(F)cc1
Product: Cn1cnc2c(Nc3ccc(F)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-fluoro-phenyl)-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: P(Br)(Br)(Br)(Br)Br.[Br:7]Br.P(Br)(Br)Br.[C:13]1([CH2:19][CH2:20][CH2:21][CH:22](O)[CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-]>C(Cl)Cl.O>[Br:7][CH:22]([CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:23]
Reactant: CC(O)CCCc1ccccc1
Reactant: BrBr
Agent: BrP(Br)(Br)(Br)Br
Agent: BrP(Br)Br
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(Br)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To phosphorus pentabromide, prepared by addition of bromine (9.0 g.) in methylene chloride (10 ml.) to phosphorous tribromide (15.0 g.) in methylene chloride (15 ml.) at 0° C., is added 5-phenyl-2-pentanol (8.2 g.) in metnhylene chloride at 0° C. The mixture is stirred for 2.5 hours at 0° C. and is then allowed to warm to room temperature. Water (50 ml.) is added, the mixture stirred for 1 hour and the methylene chloride layer separated. The extraction is repeated and the combined extracts washed with water, saturated sodium bicarbonate solution, brine and then dried over magnesium sulfate. Concentration of the dried extracts gives 12.4 g. of title product as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:16]([CH2:17][CH2:18][F:19])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[F:27][C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][CH2:18][CH2:17][N:16]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=2)[CH:7]=1
Reactant: FCCn1c(-c2ccnc(Cl)c2)c(-c2ccc(F)cc2)c2ncccc21
Reactant: Nc1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: FCCn1c(-c2ccnc(Nc3cccc(F)c3)c2)c(-c2ccc(F)cc2)c2ncccc21
Temperature: 180 °C
Yield: 38.2 %

Procedure:
In a 5 mL microwave vessel (Biotage) are weighted together 185 mg (0.5 mmole) of 2-(2-Chloro-pyridin-4-yl)-1-(2-fluoro-ethyl)-3-(4-fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridine, 67 mg (0.6 mmoles) of 3-fluorophenyl amine, 2 mg of palladium acetate, 7 mg of biphenylyl dicyclohexylphosphine and 67 mg (0.7 mmole) of sodium t-butoxide in 2.5 mL of toluene. The reaction mixture is then heated at 180° C. for 10 min. under microwave conditions. The reaction mixture is poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration the solid residue is purified by chromatography on silica gel (ethyl acetate/hexane 1/1) to give 85 mg of {4-[1-(2-Fluoro-ethyl)-3-(4-fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridin-2-yl}-(3-fluoro-phenyl)-amine as white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.[CH3:43][CH:44]([CH3:50])[CH2:45][CH2:46][C:47](Cl)=[O:48]>ClCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:47](=[O:48])[CH2:46][CH2:45][CH:44]([CH3:50])[CH3:43])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a stirred mixture of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 60 mg, 0.123 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.615 mmol) in dichloromethane (1.0 mL) at room temperature was added 4-methylvaleroyl chloride (Pfaltz & Bauer, Inc., Waterbury, Conn., USA; 20 mg; 0.15 mmol). After 1 h, the mixture was washed with 1 N HCl followed by water. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was triturated with diethyl ether, filtered, washed with diethyl ether and allowed to air dry to provide 1-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-4-methyl-pentan-1-one (32 mg, 55%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 0.87 (d, 6H, J=6.6 Hz), 1.36-1.44 (m, 2H), 1.50-1.59 (m, 1H), 1.94-2.10 (m, 4H), 2.33-2.38 (m, 2H), 2.74-2.86 (m, 1H), 3.30 (water peak and SO2CH3), 3.98-4.08 (m, 1H), 4.46-4.57 (m, 1H), 5.00-5.14 (m, 1H), 7.62 (d, 2H, J=8.5 Hz), 8.04 (d, 2H, J=8.7 Hz), 8.38 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=472.
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:11]=1[CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[C:41]([O:45][C@@H:46]([C:52]1[C:53]([CH3:95])=[N:54][C:55]2[N:56]([N:90]=[C:91]([CH:93]=O)[CH:92]=2)[C:57]=1[N:58]1[CH2:63][CH2:62][C:61]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([O:72][Si:73]([C:86]([CH3:89])([CH3:88])[CH3:87])([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[CH3:71])([CH3:64])[CH2:60][CH2:59]1)[C:47]([O:49][CH2:50][CH3:51])=[O:48])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[CH2:2]([O:9][C:10]1[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:11]=1[CH2:12][CH:13]=[CH:93][C:91]1[CH:92]=[C:55]2[N:54]=[C:53]([CH3:95])[C:52]([C@H:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:57]([N:58]3[CH2:63][CH2:62][C:61]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([O:72][Si:73]([C:86]([CH3:87])([CH3:88])[CH3:89])([C:74]4[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=4)[C:80]4[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=4)[CH3:71])([CH3:64])[CH2:60][CH2:59]3)[N:56]2[N:90]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: Fc1cc(F)c(OCc2ccccc2)c(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3cc(F)cc(F)c3OCc3ccccc3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.4 %

Procedure:
To a suspension of (2-(benzyloxy)-3,5-difluorophenethyl)triphenylphosphonium, iodide salt (330 mg, 0.519 mmol) in THF (4 ml) at 0° C. was added NaH (21.27 mg, 0.532 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to 0° C. rd (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (200 mg, 0.259 mmol) dissolved in THF (4 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h then warmed to rt and stirred 2 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-30% EtOAc/hexane) to afford (S)-ethyl 2-(2-(3-(2-(benzyloxy)-3,5-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (190 mg, 0.190 mmol, 73% yield) as mixture of E and Z isomers. LCMS (M+H)=1002.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:8]1([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[O:7][C:6]2=[O:19].C1O[C:23]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)([CH:24](Cl)[CH2:25][CH3:26])[O:22]C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:8]1([CH2:13][CH2:12][N:11]([CH2:26][CH2:25][CH2:24][C:23](=[O:22])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:10][CH2:9]1)[O:7][C:6]2=[O:19]
Reactant: CCC(Cl)C1(c2ccc(F)cc2)OCCO1
Reactant: COc1cc2c(cc1OC)C1(CCNCC1)OC2=O
Product: COc1cc2c(cc1OC)C1(CCN(CCCC(=O)c3ccc(F)cc3)CC1)OC2=O

Procedure:
Reaction of 1,3-dihydro-5,6-dimethoxyspiro[isobenzofuran-1,4'-piperidine]-3-one and α-chloro-p-fluorobutyrophenone ethylene ketal by the method described in Example 6 provides 1,3-dihydro-5,6-dimethoxy-1'-[3-(4-fluorobenzoyl)propyl]spiro[isobenzofuran-1,4'-piperidine]-3-one.