Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:13][C:14](=O)[CH2:15][CH2:16][N:17]1[C:30](=[O:31])[C:20]2([CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[O:19][C:18]21[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)CCCCCCCCCCC.CO.[NH2:46][NH2:47]>C(OC)(C)(C)C.O1CCCC1.C(Cl)(Cl)Cl>[NH:46]([C:14](=[O:13])[CH2:15][CH2:16][N:17]1[C:30](=[O:31])[C:20]2([CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:28])([CH3:29])[CH2:21]2)[O:19][C:18]21[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[NH2:47]
Reactant: NN
Reactant: CCCCCCCCCCCCOC(=O)CCN1C(=O)C2(CC(C)(C)NC(C)(C)C2)OC12CCCCCCCCCCC2
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CO
Product: CC1(C)CC2(CC(C)(C)N1)OC1(CCCCCCCCCCC1)N(CCC(=O)NN)C2=O
Temperature: 25 °C
Reaction time: 28 h

Procedure:
20-(3-Dodecyloxy-3-oxopropyl)-2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro[5.1.11.2]heneicosane-21-one (Sanduvor 3050™), 66.5 g (0.11 mole) was placed in a flask and dissolved with 150 ml methanol. To this was added 35 ml of hydrazine (54% in water) producing an immediate white precipitate. The mixture was stirred at ambient temperature for 28 hours. Most of the solvent was stripped using aspirator vacuum and the residue taken up in 100 ml methyl t-butyl ether and 175 ml tetrahydrofuran. The aqueous layer which separated was removed and the organic phase washed with three 50 ml portions of saturated sodium chloride. The organic material was dried with anhydrous magnesium sulfate, and the solvent was stripped using aspirator vacuum. The white semi-solid residue was slurried with pentane and isolated. The product weighed 39.4 g (79% of theory) and had two melting points at 171°-174° C. and 185° C. The infrared spectrum (in chloroform) showed a carbonyl band at 1680 cm-1.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.Cl.N>CO.O>[NH2:6][C:5]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[N:20]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Cc1ccc(-n2ncc(N=O)c2N)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 3.40 g (21 mmol) of 4-methylphenylhydrazine hydrochloride with a purity of 98% by weight, 1.4 ml of water, 10 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for one hour. After completion of the reaction, 15 ml of water and 5 ml of methanol were added to the mixture to cool the same up to 10° C., and 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 15 ml of cold water and dried under reduced pressure to obtain 3.26 g of 5-amino-1-(4-methylphenyl)-4-nitrosopyrazole (Isolation yield: 67.3%) as a yellowish solid with a purity of 83.5% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[S:34]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35]1>C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][N:22]([S:39]([C:36]3[CH:37]=[CH:38][S:34][CH:35]=3)(=[O:41])=[O:40])[CH2:21][CH2:20]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccsc4)CC3)c[nH]c12
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To a solution of 5-Phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (31 mg/0.067 mmol) in CHCl3 (1.0 ml) was added diisopropyl ethylamine (3 eq). The mixture was cooled to −10° C. and then added to 3-thiophenesulfonyl chloride. The solution was agitated for 1.5 h. Solid phase extraction (SPE) using an aminopropyl cartridge (500 mg) and elution with CHCl3 followed by ethyl acetate provided the title compound (19 mg 61%). LC/MS: m/z 465 Rt 2.29 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].C([Na])#N.[NH2:27][C:28]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:29]=1[CH:30]([OH:46])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:32]=1>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:27][C:28]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:29]=2[CH:30]([OH:46])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH:32]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 25 °C

Procedure:
3,5-Trans-N-(2-fluorobenzyl)-1-(N-benzyloxycarbonylpiperidin-4-yl-methyl)-5-(3-tert-butoxycarbonylaminomethylphenyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) In methanol (20 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol produced in Example 1-(2) (1.0 g) and N-benzyloxycarbonyl piperidine-4-carbaldehyde (0.82 g), followed by addition of acetic acid (0.2 g). To the mixture was added, while stirring at room temperature, cyano sodium borohydride (0.2 g). The reaction mixture was stirred for 30 minutes at 60° C., which was then concentrated. To the concentrate was added water (40 ml), followed by extraction with ethyl acetate (60 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(N-benzyloxycarbonylpiperidin-4-yl-methyl)amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (1.5 g) as a colorless oily product.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([CH2:31][O:32][CH3:33])[CH:20]=[C:19]1[C:34](=[O:37])[NH:35][CH3:36])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].Cl>O1CCOCC1>[CH2:1]([O:4][N:5]([C@@H:18]1[C:19]([C:34]([NH:35][CH3:36])=[O:37])=[CH:20][C@@H:21]([CH2:31][O:32][CH3:33])[NH:22][CH2:23]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](COC)C=C1C(=O)NC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: C=CCON([C@H]1CN[C@H](COC)C=C1C(=O)NC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 4.5 h
Yield: 68.7 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(methoxymethyl)-4-(methylcarbamoyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 256, 1 g, 1.85 mmol) in dioxane (10 ml) at room temperature was added 4M HCl in Dioxane (2 ml, 57.16 mmol). The reaction mixture was stirred at that temperature for 4-5 hours. The reaction mixture was concentrated and the crude was taken up in 2M NaOH and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Silica gel chromatography (increasing percentage of methanol in dichloromethane) afforded the title compound as a thick oil (0.56 g, 69%).
Reaction SMILES: [N:1]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6][CH2:5][C:4]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C@@H:12]3[C@@H:8]([CH2:9][CH2:10][NH:11]3)[CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[C:33]([N:11]1[C@H:12]2[C@H:8]([CH2:7][C:4]3([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=42)[CH2:5][CH2:6][N:1]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3]3)[CH2:9][CH2:10]1)(=[O:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C[C@@H]1CCN[C@@H]1c1ccccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC[C@H]2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3[C@H]21

Procedure:
The product of Step 2 (52 mg) was dissolved in dichloromethane (10 ml), treated with triethylamine (0.07 ml) and acetyl chloride (0.014 ml) for 1 h. The reaction mixture was diluted with dichloromethane, washed with water. The organic phase was concentrated to give (3aR,9bS)-tert-butyl 1-acetyl-1,2,3,3a,4,9b-hexahydrospiro[benzo[g]indole-5,4′-piperidine]-1′-carboxylate 14 (47 mg). LC-MS: m/e=329.6 (M+-tBu, 100%). Rt=3.21 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][C:22]=2[CH3:23])[CH2:13][CH2:12]1.C(C1NC(C2C=C([NH:43][C:44](=[O:46])[CH3:45])C=CC=2)=NC=1C)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[C:28]([NH:43][C:44](=[O:46])[CH3:45])[CH:27]=[CH:26][CH:25]=3)[NH:21][C:22]=2[CH3:23])[CH2:13][CH2:12]1
Reactant: Cc1[nH]c(-c2ccccc2)nc1CN1CCC(Nc2nc3ccccc3o2)CC1
Reactant: CC(=O)Nc1cccc(-c2nc(C)c(C=O)[nH]2)c1
Product: CC(=O)Nc1cccc(-c2nc(CN3CCC(Nc4nc5ccccc5o4)CC3)c(C)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described for the synthesis of example 325 (benzooxazol-2-yl-[1-(5-methyl-2-phenyl-1H-imidazol-4-ylmethyl)-piperidin-4-yl]-amine) using N-[3-(5-formyl-4-methyl-1H-imidazol-2-yl)-phenyl]-acetamide instead of 5-methyl-2-phenyl-3H-imidazole-4-carbaldehyde. MS (ESI): 445.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N+:29]=1[O-:34]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([O:21][C:20]([NH:19][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N+:29]=4[O-:34])[S:17][C:10]=23)=[C:2]([F:1])[CH:3]=1)=[O:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: [O-][n+]1ccccc1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc[n+]4[O-])sc23)c(F)c1
Yield: 57 %

Procedure:
A solution of 431 (460 mg, 0.94 mmol), 2-bromopyridine N-oxide (420 mg, 2.41 mmol), bistrimethyltin (294 μL, 465 mg, 1.42 mmol) and Pd(PPh3)4 (109 mg, 0.09 mmol) in dioxane (10 mL) was heated to reflux for 8 hrs under nitrogen. The reaction mixture was concentrated and purified by flash chromatography using the gradient 5-20% MeOH in EtOAc as an eluent yielding 432 (243 mg, 57% yield). LCMS: (M+H) 454.1.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[N:6]([CH2:7][CH:8]2[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[ClH:32]>CO>[ClH:32].[NH:10]1[CH2:11][CH2:12][O:13][CH:8]([CH2:7][N:6]2[C:5]3[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=3[N:3]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[S:2]2(=[O:31])=[O:1])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN2c3ccccc3N(c3ccccc3)S2(=O)=O)C1
Agent: Cl
Solvent: CO
Product: O=S1(=O)N(CC2CNCCO2)c2ccccc2N1c1ccccc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 2-[(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)methyl]morpholine-4-carboxylate (385 mg, 0.864 mmol) in methanol (5 mL) was added slowly an ethereal solution of hydrochloric acid (1M, 10 mL). The mixture was swirled for 20 minutes. All volatiles were removed under reduced pressure. The white precipitate was redissolved in minutesimal amount of methanol (˜1 mL). Isopropyl ether was added until the solution became slightly cloudy. The mixture was cooled to −30° C. in a freezer. The white solid formed was collected by decantation, washed with hexane and dried in vacuo to give 327 mg (99%) of 1-(morpholin-2-ylmethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide hydrochloride as a white powder. MS (ESI) m/z 345.9 ([M+H]+).
Reaction SMILES: Cl.FC(F)(F)C([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]5[O:39][CH:38]=[N:37][CH:36]=5)[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=1)=O.[Li+].[OH-]>C1COCC1.O>[NH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]5[O:39][CH:38]=[N:37][CH:36]=5)[CH:30]=4)[N:23]=3)=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Yield: 98 %

Procedure:
A solution of 2,2,2-trifluoro-N-{3-[3-(2-{[3-(1,3-oxazol-5-yl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}acetamide hydrochloride (0.68 g, 1.26 mmol) and LiOH (69 mg, 1.64 mmol) in THF (15 mL) and water (5 mL) was stirred for 6 h at 50° C. The reaction was extracted with DCM. The combined organic phases were dried over MgSO4 and evaporated down to give the title compound as a tan solid, (0.55 g, 98% yield). 1H NMR (400 MHz, d6-DMSO): δ 9.73 (s, 1H), 8.82 (d, J=6.7 Hz, 1H), 8.60 (d, J=8.9 Hz, 1H), 8.42 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 8.24 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.61 (s, 1H), 7.35-7.44 (m, 3H), 7.10-7.19 (m, 2H), 6.83 (s, 1H), 6.69-6.73 (m, 2H), 6.58 (d, J=5.3 Hz, 1H), 5.30 (bs, 2H) ppm. ES-LC/MS m/z=446 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]([C:14]1[N:15]=[C:16](S(C)(=O)=O)[N:17]([CH3:29])[C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13]>C1COCC1>[CH3:10][O:11][C:12]([C:14]1[N:15]=[C:16]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:17]([CH3:29])[C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13]
Reactant: COC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: Br[Mg]CC1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1nc(CC2CCCCC2)n(C)c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Cyclohexylmethylmagnesium bromide solution (1.77 ml; 885 μM of 0.5M solution in THF) was added dropwise to a solution of 5-benzyloxy-2-methanesulfonyl-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.26 g; 738 μM) in THF (10 ml). After stirring at room temperature for 1 h, the reaction mixture was quenched by the addition of saturated ammonium chloride solution. The product was extracted into EtOAc, washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure to give the title product as a colourless oil (0.040 g; 70%). LCMS: m/z=367 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8].[CH3:20][C@H:21]1[CH2:23][C@@H:22]1[CH2:24]Br>O1CCCC1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].C[C@H]1C[C@@H]1CBr>[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]([CH2:20][C@H:21]2[CH2:23][C@@H:22]2[CH3:24])[C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: C[C@H]1C[C@@H]1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c(C=O)c(C)c(C)n1C[C@H]1C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
Potassium tert-butoxide (3.49 g, 35.1 mmol) was added to a solution of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate (5.79 g, 31.9 mmol) and 18-crown-6 (0.41 g, 1.55 mmol) in tetrahydrofuran (130 ml) and the mixture was stirred at room temperature for 1 hour. After dropwise addition over 30 minutes of (1S,2S)-2-methylcyclopropylmethyl bromide (5.71 g, 38.3 mmol) to the reaction mixture at 50° C., the mixture was heated under reflux for 3 hours. Potassium tert-butoxide (0.36 g, 3.22 mmol) and (1S,2S)-2-methylcyclopropylmethyl bromide (0.48 g, 3.21 mmol) were further added to the mixture and this mixture was heated for 1 hour. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to afford the desired compound (8.26 g, 100%) as a pale brown oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[N:17][C:18](Cl)=[N:19][CH:20]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[Br:14][C:15]1[CH:16]=[N:17][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:19][CH:20]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Temperature: 150 °C
Yield: 96.3 %

Procedure:
In a microwave vial were mixed: 1,1-dimethylethyl 1-piperazinecarboxylate (110 mg, 0.589 mmol, available from Fluke), 5-bromo-2-chloropyrimidine (95 mg, 0.491 mmol, available from Lancaster) and DIPEA (0.112 mL, 0.638 mmol) in tert-butanol (2 mL). The reaction was stirred and heated in an Emrys Optimizer microwave at 150° C. for 0.5 hr. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer washed with brine (20 mL) before being dried through an hydrophobic frit and concentrated to yield the desired product (162.3 mg)
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:33]1C(N)=C2C(C=C(Br)C=C2)=N1)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:16]([NH2:33])=[C:15]2[C:10]([CH:11]=[C:12]([B:17]3[O:18][C:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[O:21]3)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1c2ccc(Br)cc2nn1Cc1ccccc1
Product: CC1(C)OB(c2ccc3c(N)n(Cc4ccccc4)nc3c2)OC1(C)C

Procedure:
This compound was prepared in a manner similar to the procedure described for the preparation of 2-benzyl-6-(4,4,5,5-tetramethyl-{1,3,2]dioxaborolan-2-yl)-2H-indazole (Intermediate C, step 2), using 2-benzyl-6-bromo-2H-indazol-3-ylamine in place of 2-benzyl-6-bromo-2H-indazole. 1H-NMR (300 MHz, CD2Cl2) 7.95 (s, 1H), 7.44 (dd, 1H), 7.63 to 7.29 (m, 3H), 7.29 to 7.17 (m, 3H), 5.51 (s, 2H), 3.88 (broad s, 2H), 1.36 (s, 12H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].C([N-]C(C)C)(C)C.[Li+].CCCCCC.[CH:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[OH:7][CH:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:1][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)C(C)(C)C
Reactant: CC(C)(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(=O)CC(O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of pinacolone (10 g, 100 mmol, 1), in anhydrous THF (500 mL), at −78° C. a 2.0 M solution of lithium diisopropylamide (LDA) in hexane (60 mL, 120 mmol) over a period of 30 min. The reaction was stirred at −78° C. for another 30 min. To the resulting white suspension pivalaldehyde (10.9 mL, 100 mmol) was added drop-wise via syringe and the reaction continued for another 12 hrs at room temperature. The reaction was quenched by adding 10 mL of water. Approximately 80% THF was removed and the mixture was then poured into saturated aqueous solution of NH4Cl. The aqueous layer was extracted twice with diethyl ether (200 mL) and the organic layer was washed with plenty of water. The organic layer was then dried over MgSO4 and concentrated to give a crude yellow solid of β-hydroxy ketone (17.2 g, 95%, (2)). The crude product was recrystallized from hexane to give pure white solid with a yield of 81%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32]C(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[C:50]1([CH:56]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH2:57]NC2N=C(NN)N=C3C=2N=CN3[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH2:57][CH:56]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Reactant: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Product: CCOC(=O)c1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1

Procedure:
This compound is prepared analogously to 1-[6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 168 step 3) by replacing N-[(1S,2R,3S,4R)-4-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-hydrazino-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide with N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-hydrazino-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]1[N:5]=[C:6]([C:15]([OH:29])(C)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Sn](C)(C)C)=[CH:19][C:18]=2[F:27])[N:7]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:8]=1.Br[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=1>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:31][C:2]([CH3:30])([CH3:1])[CH2:3][C:4]1[N:5]=[C:6]([C:15](=[O:29])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=3)=[CH:19][C:18]=2[F:27])[N:7]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:8]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc([Sn](C)(C)C)cc1F
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-c2ccc(F)cn2)cc1F

Procedure:
Palladium tetrakis(triphenylphosphine) (42 mg, 0.04 mmol) was added to a degassed, ambient temperature solution of 4-(2,2-dimethylpropyl)-2-{2-[2-fluoro-4-(trimethylstannyl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (200 mg, 0.37 mmol) and 2-bromo-5-fluoropyridine (129 mg, 0.74 mmol) in 1,4-dioxane (5 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.