Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:26])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.CCN(CC)CC.[F:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([Cl:41])=[O:40])=[CH:37][CH:36]=1.Cl.CCO>C(Cl)Cl>[ClH:41].[F:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([O:26][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:20]=[CH:21][C:22]([F:25])=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:40])=[CH:37][CH:36]=1
Reactant: OC(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: O=C(OC(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A cold (5° C.) mixture of 1-(4-fluorophenyl)-4-(4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-butanol monohydrochloride. (3.0 g, 7.8 mmol) and Et3N (2.40 mL, 17.2 mmol) in CH2Cl2 (55 mL) was treated dropwise (10 min) with 4-fluorobenzoyl chloride (1.11 mL, 9.4 mmol). The cooling bath was removed and the reaction mixture stirred at 23° C. for 20 h before being diluted with CH2Cl2 (250 mL). The organic solution was washed with water (30 mL), saturated Na2CO3 solution to bring pH to 9, water (30 mL) and brine, dried (MgSO4) and concentrated in vacuo to a crude mixture which was purified on silica gel column using a mixture of 20-30% AcOEt in CH2Cl2. The appropriate fractions were concentrated in vacuo to a thick syrup, 3.4 g, 93%. The free base was solubilized in EtOH and treated with HCl in EtOH (one equivalent). The solvent was removed under reduced pressure leaving a gum which was crystallized from AcOEt affording analytical sample mp 94°-8° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:15][N:16]1[CH2:20][CH:19]2[CH2:21][N:22]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:23][CH:18]2[CH2:17]1>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([N:22]3[CH2:23][CH:18]4[CH:19]([CH2:20][N:16]([CH3:15])[CH2:17]4)[CH2:21]3)=[CH:29][CH:28]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: CN1CC2CN(c3ccc(N)cc3)CC2C1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CC4CN(C)CC4C3)cc2)cc1

Procedure:
4-Butoxybenzoic acid was reacted with 4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)phenylamine by method E. The product with the molecular weight of 393.53 (C24H31N3O2); MS (ESI): 394 (M+H+) was obtained in this way.
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([CH2:24][CH3:25])=[N:15][N:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18][C:17]=23)=[CH:8][CH:7]=1.CC(C[AlH]CC(C)C)C>ClCCl>[CH2:24]([C:14]1[C:13]([CH2:12][C:9]2[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[CH2:3][OH:2])=[CH:11][CH:10]=2)=[C:17]2[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]2[N:15]=1)[CH3:25]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(/C=C/C(=O)OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(/C=C/CO)cc1
Temperature: -78 °C

Procedure:
(E)-3-[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-acrylic acid methyl ester (4) (780 mg, 2.3 mmol), was dissolved in 23 ml dichloromethane and cooled to −78° C. A 1.2M solution of DIBAH in dichloromethane (5.8 ml, 7 mmol) was added dropwise.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCCCO3)c2n1
Temperature: 60 °C

Procedure:
6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (21 mmol) is taken up as a suspension in dry ethyl acetate (50 mL). Following the addition of 4-toluenesulfonic acid monohydrate (25 mg), the mixture is heated to 60° C. and 3,4-dihydro-2H-pyran (2.5 mL) is added in drops. The reaction mixture is maintained at 60° C. for 18 hours and is then concentrated under reduced pressure. The residue is purified by flash silica gel chromatography. Following concentration of fractions, 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine is obtained. 6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.1 mmol) is coupled to 4-acetamidophenylboronic acid (0.83 g, 4.6 mmol) with tetrakis(triphenylphosphine) palladium (0) (2.5 mol %), 2 M aqueous sodium carbonate solution, and ethylene glycol dimethyl ether (DME) and under microwave irradiation (175 C, 10 min). Following an aqueous workup and flash chromatography, N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide is obtained. N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide (1.2 mmol) is taken up in dioxane (5 mL), treated with 4 M hydrogen chloride in dioxane (5 mL), and allowed to stir at room temperature for 3 days. The slurry is concentrated and purified by reverse phase preparative high performance liquid chromatography, employing a Phenomenex Prodigy 250 mm×21.2 mm 5 μm column and a 5% acetonitrile/95% water/0.1% trifluoroacetic acid to 100% acetonitrile gradient over 40 minutes. After concentration, N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide is provided.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[O:29]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:36]3[CH:37]=[C:32]([CH3:31])[CH:33]=[CH:34][CH:35]=3)[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-methylphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O3, 346.1; m/z found, 347.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.02 (s, 1H), 12.91 (s, 1H), 8.98 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.17 (d, J=7.9 Hz, 1H), 7.78 (d, J=6.3 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.24 (d, J=7.0 Hz, 1H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:13](=[O:23])[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:11]([CH3:34])=[C:10]2[C:35](N2C=CN=C2)=[O:36])=[CH:5][CH:4]=1)#[N:2].[OH:42][CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>>[C:19]([O:18][C:16](=[O:17])[CH2:15][N:14]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:10]([C:35]([O:42][CH2:43][C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])=[O:36])=[C:11]([CH3:34])[N:12]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[C:13]1=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=C(CO)OCc1ccccc1
Product: CC1=C(C(=O)OCC(=O)OCc2ccccc2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 32 %

Procedure:
The title compound is synthesized in analogy to Example 64 from Example 15A using benzyl hydroxyacetate instead of tert.-butyl-N-hydroxyethyl carbamate.
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)CCC.[CH2:38]([N:44]1[CH2:49][CH:48]2[CH:46]([C:47]2([C:51]2[CH:56]=[CH:55][CH:54]=[C:53](I)[CH:52]=2)[CH3:50])[C:45]1=[O:58])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:38]([N:44]1[CH2:49][CH:48]2[CH:46]([C:47]2([CH3:50])[C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH:52]=2)[C:45]1=[O:58])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cccs2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
To tris(dibenzylideneacetone)dipalladium (0) (4.5 mg, 4.91 lmol) in tetrahydrofuran (1 ml) at room temperature was added triphenylarsine (5.9 mg, 19.2 μmol). After 5 min, 2-(tributylstannyl)thiophene (0.10 g, 0.27 mmol) in tetrahydrofuiran (1 ml) was added followed by 3-hexyl-6-(3-iodophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 67, 78 mg, 0.19 mmol) in tetrahydrofuran (1 ml). The reaction mixture was stirred at room temperature for 16 h and then refluxed for 2 h. The cooled reaction mixture was concentrated in vacuo and chromatographed on silica gel eluting with hexane:ethyl acetate (2.1) to give the title compound as a colourless oil (68 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[Cl-].[N:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1>COCCOC>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:37][CH2:36][CH2:35][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCCN1CCCC1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NCCN4CCCC4)c3)nc12
Reaction time: 1 h

Procedure:
3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-benzoic acid 3 (110 mg, 0.39 mmol) in DME (2 mL) was treated with triethylamine (0.11 mL, 0.77 mmol) and cooled in ice bath with salt, methanolsulfonyl chloride (0.05 mL, 0.58 mmol) was added, and continue stirred for 1 hour in ice bath, then 2-pyrrolidin-1-ylethanamine (CAS 7154-73-6) (0.07 mL, 0.58 mmol) was added, the reaction was stirred overnight. The reaction mixture was purified with prep HPLC to give pure 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(2-(pyrrolidin-1-yl)ethyl)benzamide 13. LC/MS (ESI+): m/z 381 (M+H). 1H NMR (400 MHz, DMSO) δ 8.75 (t, J=5.6 Hz, 1H), 8.66-8.49 (m, 3H), 8.44 (s, 1H), 8.29 (s, 1H), 8.20 (t, J=4.4 Hz, 2H), 8.05 (s, 1H), 7.73 (d, J=9.4 Hz, 1H), 3.62-3.39 (m, 2H), 2.65 (t, J=7.0 Hz, 2H), 2.54 (s, 4H), 1.82-1.59 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=2[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[CH3:9].B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=2[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: COc1cc(CCNCc2ccccc2C(=O)NCCCCc2ccccc2)ccc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(CCNCc2ccccc2C(=O)NCCCCc2ccccc2)cc1O
Yield: 14.5 %

Procedure:
Crude 2-{[2-(3-methoxy-4-methyl-phenyl)-ethylamino]-methyl}-N-(4-phenyl-butyl)-benzamide (derived via Procedure C from 200 mg resin) is dissolved in 3 mL of dichloromethane and treated with 0.5 mL of 1 M of boron tribromide in dichloromethane for 16 h. Methanol (3 mL) is carefully added and the volatiles are removed. The crude residue is purified via semi-preparative HPLC to give 2-{[2-(3-hydroxy-4-methyl-phenyl)-ethylamino]-methyl}-N-(4-phenyl-butyl)-benzamide (28 mg). MS: m/z 417 (m+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.CN(CCN(C)C)C.[Sn:20](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH3:1][N:2]1[C:6]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:5][N:4]=[CH:3]1
Reactant: Cn1ccnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a dehydrated tetrahydrofuran solution (10 mL) of 1-methylimidazole (1.6 mL, 18.8 mmol), there was added dropwise a mixture of n-BuLi (18 mL, 45 mmol) and TMEDA (6.7 mL, 44.6 mmol) at −20° C. under nitrogen atmosphere. After stirring for 30 minutes, the mixture was raised to room temperature and stirred for another hour. After again cooling to −20° C., a solution of n-Bu3SnCl (12.5 mL, 46.4 mmol) in tetrahydrofuran (10 mL) was added dropwise thereto, the mixture was raised to room temperature and stirred for 17 hours. The reaction was terminated with water (15 mL), and then extraction was performed twice with ethyl acetate (20 mL). The mixture was then purified by silica gel chromatography (ethyl acetate:methanol=96:4) to yield the title compound (2.2 g, 32%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])(=[O:14])=[O:13])=[C:7]([CH3:31])[CH:6]=1>C1COCC1.CO>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:14])=[O:13])=[C:7]([CH3:31])[CH:6]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)OC(C)(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Temperature: 25 °C

Procedure:
NaOH (6 M, 200 ml, 1200 mmole) was added to a solution of tert.-butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetate (26.8 g, 62.7 mmole) in THF (200 ml) and methanol (200 ml). The reaction mixture was stirred at RT. After 1 hour the organic solvent was distilled off on a rotary evaporator and HCl (6 M, 210 ml) was added at 0° C. The aqueous phase was extracted with DCM (200 ml) and ethyl acetate (200 ml). The combined organic phases were dried over sodium sulfate and concentrated. Diisopropyl ether was added twice and evaporated. Yield: 21.92 g, 94%.
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH2:29][CH:30]([O:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:31])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N+]=[N-]>[Pd].CO>[C:33]([O:32][CH:30]([CH3:31])[CH2:29][CH:5]([CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][NH2:1])(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN=[N+]=[N-])CC(C)OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)CC(C)OC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A suspension of 1.617 g (2.89 mM) of 1-azido-2-(2-benzoyloxypropan-1-yl)-3-octadecylcarbamoyloxypropane m7b and 170 mg of 10% palladium on charcoal in 150 ml of methanol is hydrogenated under hydrogen atmosphere for 1 hour. The mixture is filtered and the solvent of the filtrate is evaporated to obtained crude titled compound m8.
Reaction SMILES: [I-].[C:2]1([S:8]([C:11]2[CH:29]=[CH:28][C:14]3[N:15]([C:21]4[CH:26]=[CH:25][N+:24]([CH3:27])=[CH:23][CH:22]=4)[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(O)C.[Pd]>[C:2]1([S:8]([C:11]2[CH:29]=[CH:28][C:14]3[N:15]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[n+]1ccc(N2CC(C)(C)Oc3cc(S(=O)(=O)c4ccccc4)ccc32)cc1
Agent: [Pd]
Agent: [BH4-]
Agent: [I-]
Solvent: CCO
Solvent: CO
Product: CN1CCC(N2CC(C)(C)Oc3cc(S(=O)(=O)c4ccccc4)ccc32)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A solution of 4-(7-benzenesulfonyl-2,2-dimethyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-1-methyl-pyridinium iodide (0.237 g., 0.452 mmol) in 10 mL methanol was added to a suspension of sodium borohydride (0.085 g., 2.260 mmol) in 10 mL methanol at 0C. The reaction was stirred at 0° C. for 3 hours, then stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the resulting crude solid was dissolved in a mixture of 50 mL water and 50 mL ethyl acetate. The organic phase was washed twice with 50 mL ethyl acetate, and the combined organic phase was dried over sodium sulfate and concentrated in vacuo to give 187 mg. of a yellow foam. This foam was dissolved in 20 mL ethanol and added to 25 mg. of a 5% dispersion of palladium metal on charcoal suspended in 5 mL ethanol. The suspension was purged with hydrogen gas and maintained at a pressure of 55 psi for 48 hours. The reaction mixture was filtered through celite, concentrated in vacuo and purified by flash chromatography (12:1:0.1 CH2Cl2:MeOH:NH4OH) to give 114 mg (63%) of 7-benzenesulfonyl-2,2-dimethyl-4-(1-methyl-piperidin-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine as a clear oil. MS: 401 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[C:9]1([O:18]O)[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1.S([O-])([O-])(=O)=O.[Mg+2]>S(=O)(=O)(O)O.C(O)C>[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][CH:13]1[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9](=[O:18])[CH2:14]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: O=C1CCCCC1
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 0.17 h

Procedure:
To a stirred mixture of cyclohexanone (19.6 g.) and ethanol (50 c.c.), kept at or below 0°C, was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g., 78% pure); solution was complete in ca. 10 min. To the solution was added conc. sulphuric acid (3 drops) and magnesium sulphate and the mixture was stored at 0°C for 3 days. The solid was filtered off, the filtrate washed with water, dried and distilled, to give cyclohexanone, dihydroisophorone and a fraction (11.5 g.), b.p. 90° - 100° at 0.02 mm.Hg., peroxide equivalent 179. By mass spectroscopy the product was shown to contain the unsymmetrical peroxide ##SPC32##
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH:5]([CH3:14])[CH2:6][C:7]2=[O:13].CCN(CC)CC.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[Br:1][C:2]1[C:3]2[CH2:4][CH:5]([CH3:14])[CH2:6][C:7](=[O:13])[C:8]=2[C:9]([O:12][S:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)(=[O:29])=[O:28])=[CH:10][CH:11]=1
Reactant: CC1CC(=O)c2c(O)ccc(Br)c2C1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CC(=O)c2c(OS(=O)(=O)c3cccs3)ccc(Br)c2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.7 %

Procedure:
To a solution of 5-bromo-8-hydroxy-3-methyl-1,2,3,4-tetrahydronaphthalen-1-one (Intermediate 1, Step 1) (0.2 g, 0.78 mmol) in DCM (10 mL) was added Et3N (1.1 mL, 7.8 mmol) and thiophene-2-sulphonyl chloride (0.57 g, 3.1 mmol). This mixture was stirred at room temperature for 5 h, and then partitioned with DCM (20 mL) and water (20 mL). The two phases were separated and the aqueous phase extracted with DCM (20 mL). The combined organic phases were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel eluting with EtOAc:hexane (10:90-35:65) to afford the title compound (0.24 g, 75%) as an orange solid. mp 110-113° C. 1H NMR (360 MHz, CDCl3) δ 1.14(3H,d, J=6.0 Hz), 2.10-2.30(2H,m), 2.48-2.62(2H,m) 3.16-3.22(1H,m), 7.02(1H,d, J=8.7 Hz), 7.14(1H,dd, J=3.8, 4.9 Hz), 7.69-7.76(3H,m). MS(ES+) 401/403 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([N:24]([CH3:26])[CH3:25])=[O:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:19][C:20]3[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=3[C:22](=[O:23])[N:24]([CH3:25])[CH3:26])[N:3]=2)[NH:8][CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CN(C)C(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccccc1Nc1cnc2[nH]cc(C(=O)NC(C)(C)C)c2n1
Temperature: 140 °C
Yield: 15.7 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 269 μmol), 2-amino-N,N-dimethylbenzamide hydrochloride (81.0 mg, 404 μmol), BINAP (8.38 mg, 13.5 μmol), palladium (II) acetate (15.1 mg, 67.3 μmol) and sodium tert-butoxide (77.6 mg, 808 μmol, Eq: 3) in DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (15-45% dichloromethane/[10% dichloromethane/methanol/0.5% ammonium hydroxide]) gave N-tert-butyl-2(2(dimethylcarbamoyl)phenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (16 mg, 42.1 μmol, 16%) as an off-white solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.25 (s, 1H), 8.77 (s, 1H), 8.06 (s, 1H), 7.96 (d, J=3.0, 1 H), 7.91 (d, J=7.9, 1 H), 7.78 (s, 1H), 7.38 (t, J=7.7, 1 H), 7.30 (d, J=7.5, 1 H), 7.11 (t, J=7.5, 1 H), 2.88 (s, 3H), 2.80 (s, 3H), 1.27 (s, 9H); MS (EI/CI) m/z: 381.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: CC(C)CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
6-Amino-9-benzyl-2-(isobutylamino)purine (75 mg, 0.25 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent of the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (62 mg, yield 65%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:2].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[N:5]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:2]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)c1c(C=O)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1

Procedure:
React 3-formyl-2-carboethoxy-4,6-dichloroindole with p-toluenesulfonyl chloride as describe in Preparation 1.1 to give the title compound.