Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[N:41][CH:42]=2)O1>>[C:46]([O:45][C:44](=[O:50])[NH:43][C:40]1[CH:39]=[CH:38][C:37]([C:2]2[N:7]3[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:4][CH:3]=2)=[CH:42][N:41]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Yield: 48 %

Procedure:
Compound 2b (500 mg, 1.15 mmol) was subjected to Suzuki coupling conditions with tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-ylcarbamate using the reaction conditions described in Example 1, Step G to obtain compound 13a as a yellow solid (300 mg, 48% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H31N7O3: 550.2 (M+H). Found 550.2.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][C:8]3[NH:14][C:13](=O)[C:12]4[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=4[S:10][C:9]=3[CH:20]=[C:5]2[O:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[N:21]1([C:13]2[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10][C:9]3[CH:20]=[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]4=[CH:7][C:8]=3[N:14]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: O=C1Nc2cc3c(cc2Sc2ccccc21)OCCO3
Reactant: C1CNCCN1
Product: c1ccc2c(c1)Sc1cc3c(cc1N=C2N1CCNCC1)OCCO3
Yield: 5.4 %

Procedure:
2,3-Dihydro-1,4-benzodioxino[6,7-b][1,4]benzothiazepin-11(12H)-one (29 mg, 0.1 mmol) and piperazine (43 mg, 0.5 mmol) were reacted according to GP4 to give 1.9 mg of the title compound (160FE17B). MS (ESI) 354 (MH+). Purity for MH+ (UV/MS) 99/95.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.Cl.[NH:34]1[CH2:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.O>[N:34]1([C:16]([C:13]2[CH:12]=[N:11][C:10]([O:9][C:8]3[CH:19]=[C:20]([C:22]4[NH:23][C:24]([C:27]5[S:28][CH:29]=[CH:30][N:31]=5)=[CH:25][CH:26]=4)[CH:21]=[C:6]([O:5][C@@H:4]([CH3:32])[CH2:3][O:2][CH3:1])[CH:7]=3)=[CH:15][N:14]=2)=[O:18])[CH2:37][CH2:36][CH2:35]1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 95.5 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazine-2-carboxylic acid (28.0 mg, 0.062 mmol) synthesized in Example (63a) was dissolved in tetrahydrofuran (3 mL), and azetidine hydrochloride (17.4 mg, 0.186 mmol), HATU (35.3 mg, 0.093 mmol) and N,N-diisopropylethylamine (65 μL, 0.37 mmol) were added, followed by stirring at room temperature for 28 hours under nitrogen atmosphere. To the reaction solution, water (15 mL) was added, and extraction was carried out with ethyl acetate (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using preparative TLC (developing solvent: methanol/dichloromethane=15%) to afford the desired compound (29.1 mg, yield 96%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([C:21](OC)=[O:22])=[C:16]([CH3:25])[C:15]=3[CH:26]=2)=[O:9])=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C1COCC1>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([CH2:21][OH:22])=[C:16]([CH3:25])[C:15]=3[CH:26]=2)=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)C1=C(C)c2cc(NC(=O)c3ccc(Cl)cn3)ccc2CCC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(CO)CCCc2ccc(NC(=O)c3ccc(Cl)cn3)cc21
Temperature: -78 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
To a solution of methyl 2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from step 3A (345 mg, 0.930 mmol) in THF (2 mL) was slowly added 1.0 M DIBAL-H/THF (4.65 mL, 4.65 mmol) at −78° C. The mixture was stirred at −78° C. for 4 h and then allowed to warm to rt. Brine was added slowly to quench the reaction. The reaction mixture was then extracted with 3×100 mL of EtOAc and the organic layers were combined, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (hexanes-60% EtOAc) to give a clean (E)-5-chloro-N-(8-(hydroxymethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide (120 mg, 0.350 mmol, 37.6% yield). LCMS (M+H)+=343.2. 1H NMR (500 MHz, chloroform-d) δ 9.81 (s, 1H), 8.56 (dd, J=2.3, 0.6 Hz, 1H), 8.25 (dd, J=8.4, 0.6 Hz, 1H), 7.87 (dd, J=8.4, 2.3 Hz, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.55 (dd, J=8.1, 2.3 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 4.39 (s, 2H), 2.54 (t, J=7.0 Hz, 2H), 2.14 (s, 3H), 2.10 (quin, J=7.1 Hz, 2H), 2.01-1.95 (m, 2H)
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].CO>O>[CH3:21][O:22][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2s1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzothiazole, 0.28 g of potassium carbonate and 3 ml of methanol was refluxed with heating for 1.5 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzothiazole (hereinafter, referred to as the present compound 4).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC#N>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:12][CH3:13])[CH2:7][CH2:6]1
Reactant: CCC(NC(C)=O)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: CCC(NC(C)=O)C1CCC(=O)CC1

Procedure:
A solution of N-(1-1,4-dioxaspiro[4.5]decan-8-ylpropyl)acetamide (as prepared in the previous step, 39 mg, 0.16 mmol, 1.00 equiv) in CH3CN (5 mL) and HCl (1M, 1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of aq. sodium bicarbonate (1M). The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1/[CH:11]=[CH:12]/[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(Cl)Cl.[H][H]>CO.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: Cn1c(/C=C/c2ccc(C#N)cc2)cc2ccccc21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cn1c(CCc2ccc(C#N)cc2)cc2ccccc21

Procedure:
2.3 g (8.9 mmol) of (E)-4-[2-(1-methyl-indol-2-yl)ethenyl]benzonitrile are dissolved in 150 ml methanol and 50 ml methylene chloride and hydrogenated with 0.20 g 10% palladium on charcoal at 3 bar hydrogen pressure. The solvent is distilled off in vacuo, the white residue obtained is washed with a little diethylether and acetone.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:23]=[N:24][N:25](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:26]=5)=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1>C(O)=O>[NH:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[CH:11][C:10]([N:5]4[CH2:6][CH2:7][C@@H:8]5[CH2:9][N:2]([CH3:1])[CH2:3][C@H:4]45)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[CH:26]=[N:25]1
Reactant: CN1C[C@H]2CCN(c3ccc(-c4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc4)cc3)[C@H]2C1
Solvent: O=CO
Product: CN1C[C@H]2CCN(c3ccc(-c4ccc(-c5cn[nH]c5)cc4)cc3)[C@H]2C1

Procedure:
The product of Example 81A (44 mg, 0.075 mmole) was stirred with 3 ml of formic acid for 4 hours. The mixture was concentrated to dryness and the residue was dissolved in 10% methanol in dichloromethane and stirred with saturated sodium bicarbonate. Two layers were separated and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.88 (s, 2H) 7.47-7.64 (m, 6H) 6.65 (d, J=8.81 Hz, 2H) 4.11-4.25 (m, 1H) 3.50-3.66 (m, 1H) 3.25-3.37 (m, 1H) 2.92-3.07 (m, 1H) 2.71-2.82 (m, 1H) 2.51-2.69 (m, 3H) 2.34 (s, 3H) 2.13-2.25 (m, 1H) 1.90-2.05 (m, 1H). MS: (M+H)+=345.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>O.C(Cl)Cl.CO>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CCN1CCNCC1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 2-fluoro-4-nitrobenzene (3.2 mL, 29.7 mmol) and 1-ethylpiperazine (7.6 mL, 59.4 mmol, 2 equiv) was heated to reflux for 117 h. After cooling to rt, the reaction mixture was diluted with H2O and DCM/MeOH, 9:1. The aqueous layer was separated and extracted with DCM/MeOH, 9:1. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 1:0→95:5) afforded 6 g of the title compound as a brown oil: ESI-MS: 236.0 [M+H]+; tR=2.49 min (System 1); TLC: Rf=0.26 (DCM/MeOH, 95:5).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:11]([OH:17])[CH2:12][CH2:13][CH2:14][C:15]#[CH:16]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(OC(=O)C)C>[N:6]1[CH:7]=[CH:8][C:3]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][CH2:11][OH:17])=[CH:4][CH:5]=1
Reactant: C#CCCCCO
Reactant: Brc1ccncc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: Cl
Solvent: CCOC(C)=O
Product: OCCCCC#Cc1ccncc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
4-bromopyridine hydrochloride (5 g, 25.7 mmol) was partitioned between sodium hydroxide (20 ml, 40.0 mmol) and ethylacetate (3×100 ml). The organic layer was separated, dried over Na2SO4 and evaporated in vacuo. The resulting oil was dissolved in triethylamine (10 ml) and degassed under nitrogen. 5-Hexyn-1-ol, (2.8 ml, 25.8 mmol) was added followed by bis(triphenylphosphine)palladium (II) chloride, (200 mg, 0.285 mmol) and copper(I)iodide (100 mg, 0.525 mmol) and the resulting mixture was stirred and heated under reflux for 20 mins. when a dark brown sludge was obtained. The mixture was cooled to rt and partitioned between EtOAc (200 ml) and water (50 ml). The aqueous phase was extracted with EtOAc (2×100 ml), combined the organic extracts, dried (Na2SO4), filtered and evaporated in vacuo. The resulting dark brown gum was purified by column chromatography, the sample was loaded onto silica (100 g) in dichloromethane and eluted using a gradient of 0-100% ethyl acetate in cyclohexane over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (2.36 g). LCMS (System D): tRET=1.85 min; MH+ 176
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:19]([NH2:22])[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>>[CH2:19]([NH:22][C:2]1[N:3]=[C:4]([NH:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:20]=[CH2:21]
Reactant: C=CCN
Reactant: Cc1csc2c(NN3CCCCC3)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NN2CCCCC2)c2scc(C)c2n1
Yield: 64 %

Procedure:
339 mg (1.2 mmol) of 2-chloro-7-methyl-4-piperidinoaminothieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 233 mg (yield: 64.0%) of the title compound.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C2C(=CC=C([C@H]3[C@@]4(C5C(=CC=CC=5)N([CH2:43][CH2:44][O:45][CH3:46])C4=O)C3)C=2)C=N1>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:43][CH2:44][O:45][CH3:46])[C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: COCCN1C(=O)[C@@]2(C[C@H]2c2ccc3cn[nH]c3c2)c2ccccc21
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Product: COCCN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)n[nH]c3c2)c2ccccc21
Yield: 66 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (1R,2S)-2-(1H-indazol-6-yl)-1′-(2-methoxyethyl)spiro[cyclopropane-1,3′-indolin]-2′-one (260 mg, 0.779 mmol). Purification using 0-30% EtOAc in hexane on Biotage Isolera with SNAP 25 g column yielded the title compound as a white solid (235 mg, 66%; 98% e.e.) with the major (1R,2S) enantiomer eluting at 2.6 min (Phenomenex Lux 5μ Amylose-2 150×4.6 mm, 2.5 mL/min with isocratic at 20% EtOH in hexane for 0.5 min, then gradient 20-50% EtOH in hexane over 2.5 min, then isocratic at 50% for 1 min). From the racemic reference standard, the retention time of the (1S,2R) enantiomer was 3.2 min using this method. 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.34 (s, 1H), 7.14 (t, J=7.6 Hz, 1H), 7.06-7.01 (m, 2H), 6.63 (t, J=7.2 Hz, 1H), 5.87 (d, J=7.6 Hz, 1H), 4.14-3.97 (bm, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.46 (t, J=7.6 Hz, 1H), 3.39 (s, 3H), 2.28-2.26 (m, 1H), 2.05-2.01 (m, 1H); MS ESI 460.1 [M+H]+, calcd for [C20H18IN3O2+H]+ 460.0. Optical Rotation: [α]22D=−239° (c 0.243, MeOH).
Reaction SMILES: [CH:1]1([CH:4]([OH:19])[C@H:5]2[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([C:4]([C@H:5]2[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:19])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(O)C2CC2)COC1(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](C(=O)C2CC2)COC1(C)C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of (R)-tert-butyl 4-(cyclopropyl(hydroxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 230, 12.47 g, 45.95 mmol) in DCM (300 mL) at room temperature was added Dess-Martin periodinane (29.2 g, 68.93 mmol). The reaction mixture was stirred overnight then diluted with ethyl acetate and washed with saturated sodium bicarbonate. An emulsion formed and was filtered through celite. The layers were separated and the organics washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound as a colorless oil (11.15 g, 90%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 22.5 h
Yield: 52.7 %

Procedure:
A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.0 g, 11.5 mmol) in dimethylformamide (50 mL) was treated with cesium carbonate (5.62 g, 17.25 mmol) and triphenylmethyl chloride (3.85 g, 13.8 mmol). The reaction mixture was stirred at 70° C. for 22.5 h under a nitrogen atmosphere. Cesium carbonate (3.75 g, 11.5 mmol) and triphenylmethyl chloride (3.2 g, 11.5 mmol) were added to the reaction mixture and was stirred for 6.5 h. The reaction mixture was added to ice water. The precipitate was filtered and washed with water. The product, 3-iodo-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, was dried over night on the lyophilizer. The resulting solid was triturated with ethyl acetate to give 3.05 g (53%) of 3-iodo-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 7.3190-7.1106 (m, 16H); TLC (Baker Pre-coated Hard Layer Silica Gel TLC plates, Si250F254, 30% Ethyl acetate in heptane) Rf=0.33.
Reaction SMILES: C(O)(=O)C.C([O:7][C:8](=[O:23])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=O)=O)=[CH:13][C:12]=1[CH2:21][CH3:22])C.Cl[Si](Cl)(C)C.[CH3:29][C:30]1[O:31][C:32]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)=[CH:33][C:34]=1[CH2:35]O>C(OCC)(=O)C.[Zn]>[CH2:21]([C:12]1[CH:13]=[C:14]([S:17][CH2:35][C:34]2[CH:33]=[C:32]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:41][CH:42]=3)[O:31][C:30]=2[CH3:29])[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][C:8]([OH:7])=[O:23])[CH3:22]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1CC
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCc1cc(SCc2cc(-c3ccc(C(F)(F)F)cc3)oc2C)ccc1OCC(=O)O
Temperature: 60 °C

Procedure:
To a mixture of zinc (407 mg) in ethyl acetate (10 ml) stirred at 60° C. was added acetic acid (0.203 ml) followed by a solution of ethyl[4-(chlorosulfonyl)-2-ethylphenoxy]acetate (intermediate 111, 546 mg) in ethyl acetate. The reaction mixture was stirred 60° C. for 2 hours and then dichlorodimethylsilane (0.431 ml) was added drop-wise. After a further 90 minutes {2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (472 mg) was added and the reaction mixture stirred at reflux for 17 hours. The reaction mixture was diluted with ethyl acetate; extracted with water, saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulfate. An attempt was purify the crude material by Biotage® chromatography using 3:2 petroleum ether: ethyl acetate as eluent. The partially purified material (223 mg) was hydrolyzed in 1,4-dioxan (6 ml) using 0.5 M aqueous sodium hydroxide (1.86 ml) for 16 hours. The reaction mixture was neutralized with 50W×2-200 Dowex; evaporated and the residue purified by mass-directed autopreparative HPLC to give the title compound as a solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:11][C:10]2[C:9](=[O:12])[N:8]([CH3:13])[C:7]3=[N:14][C@@H:15]4[CH2:19][CH2:18][CH2:17][C@@H:16]4[N:6]3[C:5]=2[N:4]=1.[CH3:20]I>>[CH3:2][C:3]1[N:11]([CH3:20])[C:10]2[C:9](=[O:12])[N:8]([CH3:13])[C:7]3=[N:14][C@@H:15]4[CH2:19][CH2:18][CH2:17][C@@H:16]4[N:6]3[C:5]=2[N:4]=1
Reactant: Cc1nc2c([nH]1)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12
Reactant: CI
Agent: Cl
Product: Cc1nc2c(n1C)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12

Procedure:
By using cis-5,6a,7,8,9,9a-hexahydro-2,5dimethylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one hydrochloride, and methyl iodide instead of 4-chlorobenzyl chloride in accordance with Example 21, the title compound is obtained.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)[OH:4].Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>C1(C)C=CC=CC=1.N1C=CC=CC=1.CCOCC.O>[CH:30]([O:29][C:27]([N:20]1[C:21]2[C:17](=[CH:16][C:15]([C:3]([C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]([CH3:14])[CH:6]=3)([OH:4])[C:2]([F:1])([F:24])[F:25])=[CH:23][CH:22]=2)[CH:18]=[N:19]1)=[O:28])([CH3:32])[CH3:31]
Reactant: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Reactant: CC(C)OC(=O)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)OC(=O)n1ncc2cc(C(O)(c3cn(C)c4ccccc34)C(F)(F)F)ccc21
Temperature: 85 °C

Procedure:
A mixture of 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol (0.165 mmol) and isopropyl chloroformate (0.49 mmol from a 1.0 M solution in toluene) in 1 mL of pyridine was heated at 85° C. for 10 hours, cooled to room temperature, and diluted with ether and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The volatiles were concentrated in vacuo and the residue purified by flash silica gel chromatography using 33% ethyl acetate in hexanes. The product-rich fractions were concentrated in vacuo to afford 0.069 mmol of the desired compound, m.p. 105° C.-106° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl.[CH3:16][N:17]([CH3:32])[S:18]([C:21]1[CH:31]=[CH:30][C:24]2[NH:25][C:26]([CH2:28]Cl)=[N:27][C:23]=2[CH:22]=1)(=[O:20])=[O:19]>CN(C)C=O>[CH3:32][N:17]([CH3:16])[S:18]([C:21]1[CH:31]=[CH:30][C:24]2[NH:25][C:26]([CH2:28][O:10][C:8]3[CH:9]=[C:2]([F:1])[C:3]([CH:4]=[O:5])=[CH:6][C:7]=3[O:11][CH3:12])=[N:27][C:23]=2[CH:22]=1)(=[O:19])=[O:20]
Reactant: CN(C)S(=O)(=O)c1ccc2[nH]c(CCl)nc2c1
Reactant: COc1cc(C=O)c(F)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(F)cc1OCc1nc2cc(S(=O)(=O)N(C)C)ccc2[nH]1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 16.6 %

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (39, 0.38 g, 2.2 mmol) was dissolved in N,N-dimethylformamide (30 mL) and sodium hydride 60% dispersion in mineral oil (120 mg) was added. After 20 minutes, 2-chloromethyl-1H-benzoimidazole-5-sulfonic acid dimethylamide hydrochloride salt (217, 0.559 g, 1.80 mmol) was added to the mixture. The reaction was stirred at 60° C. overnight. The solvent was removed under reduced pressure. Ethyl acetate was added and the organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with a gradient of ethyl acetate (20-100%) in hexane to provide the desired compound (218, 0.122 g, 17%).