Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[N:23]=[CH:22][CH:21]=[CH:20][C:13]=1[C:14]([NH:16][CH2:17][C:18]#[CH:19])=[O:15].[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:29]=1)=[N+:25]=[N-:26].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[N:23]=[CH:22][CH:21]=[CH:20][C:13]=1[C:14]([NH:16][CH2:17][C:18]1[N:26]=[N:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=2)[CH:19]=1)=[O:15]
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1OC
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(Nc2ncccc2C(=O)NCc2cn(Cc3cccc(Oc4ccccc4)c3)nn2)c(OC)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 78 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 2,4-dimethoxyaniline (9 g, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10g as pure product. To a solution of 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10 g, 150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.004 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1g (201 mg, 78%); mp: 127-129° C.; 1H NMR (300 MHz, CDCl3) δ 10.30 (s, 1H), 8.25-8.21 (m, 2H), 7.73 (d, J=7.5 Hz 1H), 7.56 (s, 1H), 7.35-7.28 (m, 3H), 7.11 (t, J=7.5 Hz, 1H), 6.99-6.90 (m, 5H), 6.59-6.47 (m, 3H), 5.45 (s, 2H), 4.67 (d, J=5.2 Hz, 2H), 3.87 (s, 6H), 3.79 ppm (s, 3H); MS (ESI m/z): 537 [M+H]+. Yield: 78%
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[N:21]=[C:20]2[NH:22][N:23]=[CH:24][C:19]2=[C:18]([N:25]2[CH2:31][CH:30]3[O:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:17]=1.[O:33]1[C:37]2([CH2:42][CH2:41][CH:40](O)[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:15][C:16]1[N:21]=[C:20]2[N:22]([CH:40]3[CH2:41][CH2:42][C:37]4([O:33][CH2:34][CH2:35][CH2:36]4)[CH2:38][CH2:39]3)[N:23]=[CH:24][C:19]2=[C:18]([N:25]2[CH2:31][CH:30]3[O:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:17]=1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Reactant: OC1CCC2(CCCO2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCC4(CCCO4)CC3)c2n1
Temperature: 25 °C

Procedure:
Diisopropyl azodicarboxylate (2.6 mL, 13 mmol) was added in drops to a mixture of 3-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (2.6 g, 10 mmol), 1-oxaspiro[4.5]decan-8-ol (U.S. Pat. No. 4,438,130, Mar. 20, 1984, 1.6 g, 11 mmol), and triphenylphosphine (2.9 g, 11 mmol) in tetrahydrofuran (80 mL). After stirring at room temperature, the mixture was purified by reverse phase high performance liquid chromatography on a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 15% acetonitrile/85% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide two separable diastereomers of 3-(6-chloro-1-(1-oxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane. MS (ES+): 404.2 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.C(NC1NC2C(N=C(OC)N=2)=C(N)N=1)CCC.C(=O)([O-])[O-].[K+].[K+].N1CCCCCC1.C(N(CC)CC)C.[CH2:45]([NH:49][C:50]1[N:58]=[C:57]2[C:53]([N:54]=[C:55]([O:71]C)[N:56]2[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][N:64]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]2)=[C:52]([NH2:73])[N:51]=1)[CH2:46][CH2:47][CH3:48]>CN(C=O)C>[NH2:73][C:52]1[N:51]=[C:50]([NH:49][CH2:45][CH2:46][CH2:47][CH3:48])[N:58]=[C:57]2[C:53]=1[NH:54][C:55](=[O:71])[N:56]2[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][N:64]1[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCCN3CCCCCC3)c2n1
Agent: C1CCCNCC1
Agent: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCCCN3CCCCCC3)c2n1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
N2-Butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (192 mg, 0.547 mmol) and potassium carbonate (189 mg, 1.368 mmol) were suspended in DMF (3 ml) and heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and1-bromo-5-chloropentane (0.072 ml, 0.547 mmol) was added and the reaction stirred for a further 18 hours. Hexahydro-1H-azepine (54.2 mg, 0.547 mmol) and triethylamine (0.076 ml, 0.547 mmol) were added and the reaction mixture heated to 70° C. for 24 hours. LCMS showed a major peak with MH+ 404 consistent with the formation of N2-butyl-9-[5-(hexahydro-1H-azepin-1-yl)pentyl]-8-(methyloxy)-9H-purine-2,6-diamine. The solvent was removed in vacuo and the residue partitioned between DCM (2 ml) and water (2 ml). The aqueous was extracted again with DCM (2 ml) and the combined organic extracts were concentrated and the residue was dissolved in 1:1 MeOH:DMSO (2 ml) and purified by MDAP (Method C). Evaporation of the product containing fractions gave a residual TFA salt which LCMS indicated had undergone hydrolysis of the 8-methoxy group, presumably on concentration in the presence of TFA. This crude material was dissolved once more in 1:1 MeOH:DMSO (2 ml) and re-purified by MDAP (Method A). Product-containing fractions were evaporated under a stream of nitrogen to give the title compound as a white solid (39 mg).
Reaction SMILES: C([O:8][C:9]([CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:10])C1C=CC=CC=1>[Pd].CO>[C:9]([CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])([OH:10])=[O:8]
Reactant: COC(=O)c1cc(O)cc(OCC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(O)cc(OCC(=O)O)c1
Yield: 103.5 %

Procedure:
10% palladium on carbon (0.1 g) was added to a mixture of methyl 3-benzyloxycarbonylmethoxy-5-hydroxybenzoate (1 g) in methanol (20 ml) and the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give methyl 3-carboxymethoxy-5-hydroxybenzoate (0.74 g).
Reaction SMILES: [CH2:1]([N:11]=[C:12]=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].C(Cl)(=O)CCCCCCCCC=C.[CH2:27]([O:34][NH2:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCCl>[CH2:1]([NH:11][C:12]([NH:35][O:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: NOCc1ccccc1
Reactant: C=CCCCCCCCCN=C=O
Agent: C=CCCCCCCCCC(=O)Cl
Solvent: ClCCCl
Product: C=CCCCCCCCCNC(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 9-decenyl isocyanate, prepared as in Example 18 above from 10.8 ml of 10-undecenoyl chloride in 1,2-dichloroethane (150 ml) at room temperature was added benzyloxyamine (7.2 g). After 20 minutes, the mixture was evaporated, hexane (50 ml) was added, and the mixture cooled to 0° C. The resulting solids were collected by filtration, to provide N-(9-decenyl)-N'-benzyloxyurea as a white solid (7.14 g, mp 53°-55° C.). To a stirred slurry of this urea (3.50 g, 11.65 mmol) in DMF (35 ml) at room temperature under nitrogen was added sodium hydride (490 mg of a 60% dispersion in oil). After one hour, 1,3-dibromopropane (1.45 ml) was added, and the reaction was stirred for two hours. The mixture was poured into 1% aqueous HCl (200 ml), and extracted twice with ether. The combined extracts were washed with water, dried (MgSO4), filtered and evaporated. Purification by chromatography on silica gave 3-decyl-1-benzyloxy-3,4,5,6-tetrahydro-lH-pyrimidin-2-one as a colorless oil (1.92 g, 48% yield). Hydrogenolysis as in Example 2 above provided the title compound as a light magenta solid, after recrystallization from carbon tetrachloride, mp 45°-46° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1.[C:15]([PH:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CO>[C:15]([P:19]([CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)PC(C)(C)C
Reactant: ClCc1cccc(-c2ccccn2)n1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)P(Cc1cccc(-c2ccccn2)n1)C(C)(C)C
Temperature: 50 °C
Yield: 84.9 %

Procedure:
To an oven dried 50 mL pressure vessel equipped with magnetic stirring bar was added 6-chloromethyl-2,2′-bipyridine (BPy-CH2Cl) (2.05 g, 10.00 mmol), di-tert-butyl phosphine (1.75 g, 12.00 mmol), and 30 mL MeOH in a nitrogen glove box. The flask was sealed and heated at 50° C. for 48 hrs with stirring outside the glove box. After cooling, it was reintroduced to the glove box, triethylamine (1.82 g, 18.00 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr. The solvents were removed under reduced pressure to obtain a white solid. The residue was washed with ether (3×20 mL) and the ether filtered and was removed under reduced pressure to yield a white solid. It was recrystallized from MeOH at ca. −30° C. to yield 2.67 g (85%) of 6-di-tert-butylphosphinomethyl-2,2′-bipyridine (BPy-tPNN).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].CO[C:13](=O)[C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][C:17]([C:22]2[C:27]([CH2:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:30][CH3:31])=[N:16][C:15]=1[Cl:32].CCO[CH2:37][CH3:38]>>[Cl:32][C:15]1[C:14]([CH2:13][N:16]([CH3:17])[C@@H:15]2[C:37]3[C:38](=[CH:27][CH:22]=[CH:23][CH:24]=3)[CH2:18][CH2:19][CH2:14]2)=[C:19]([CH2:20][CH3:21])[CH:18]=[C:17]([C:22]2[C:27]([CH2:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:30][CH3:31])[N:16]=1
Reactant: CCOCC
Reactant: CCc1cc(-c2c(CC)cccc2CC)nc(Cl)c1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: CCc1cc(-c2c(CC)cccc2CC)nc(Cl)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of LiAlH4 (1M in TI-RF, 3 mL) in ether (10 mL) is treated with AlCl3 (133 mg) under nitrogen. After 30 minutes, 2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester (250 mg) in 5 mL of ether is added. The resulting mixture is heated at reflux for 2 hours. On cooling, Na2SO4.10H2O (1.0 g) is added. The mixture is stirred at room temperature for one hour and filtered through Celite. The filtrate is concentrated in vacuo. CH2Cl2 (5 mL) and SOCl2 (0.5 mL) are added to the residue. The resulting mixture is stirred at room temperature for one hour. The volatile material is removed in vacuo. K2CO3 (500 mg) and (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (200 mg) in DMF (5 ml) are added to the residue and the reaction mixture is stirred at room temperature overnight. Hexane (20 mL) and water (5 mL) are added to the mixture. The organic layer is separated, washed once with brine, dried (Na2SO4) and concentrated. The crude product is purified by PTLC (4:1 hexane/EtOAc) to give (S)-[2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-pyridin-3-ylmethyl]-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine. 1H NMR (CDCl3) 7.62 (d, 1H), 7.11-7.30 (m, 7H), 4.02 (m, 3H), 3.01 (m, 2H), 2.80 (m, 2H), 2.39 (m, 4H), 2.15 (m, 5H), 1.85-2.00 (m, 2H), 1.33 (t, 3H), 1.09 (t, 6H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][OH:4].[N:14]#[C:15]Br>>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C@@H:2]2[CH2:3][O:4][C:15]([NH2:14])=[N:1]2)=[CH:12][CH:11]=1
Reactant: N#CBr
Reactant: N[C@@H](CO)CCc1ccc(F)cc1
Product: NC1=N[C@H](CCc2ccc(F)cc2)CO1

Procedure:
In analogy to example 1b (R)-2-amino-4-(4-fluoro-phenyl)-butan-1-ol was reacted with cyanogen bromide to give (R)-4-[2-(4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 209.3 ([M+H]+))
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:27])[CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12]C)=[CH:7][CH:6]=2.B(Br)(Br)Br>C(Cl)Cl>[OH:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:27])[CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=1)=[C:3]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COc1ccc2c(Oc3ccc(NC(=O)CC(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(NC(=O)CC(=O)O)cc2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
Compound 42 (75 mg, 0.17 mmol, 1 equiv) was dissolved in CH2Cl2 (5 mL) and cooled to 0° C. under N2. BBr3 (80 μL, 0.85 mmol, 5 equiv) was added dropwise and the resulting solution was allowed to stir at 0° C. for 2 h. The reaction mixture was then poured into ice and product extracted into EtOAc (250 mL). The organics were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (0 to 100% CH3CN in water w/0.1% TFA) to provide the title compound (43) (22 mg, 30%) as a tan solid. 1HNMR (400 MHz, DMSO-d6): δ 10.66 (br s, 1H) 10.36 (br s, 1H), 7.87 (s, 1H), 7.57 (m, 1H), 7.32-7.15 (m, 9H), 6.56 (m, 2H), 2.52 (s, 2H), 2.21 (s, 3H). MS m/z 428.5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([O:12]CC2C=CC=CC=2)[CH:3]=1>C(O)C.[Pd]>[OH:12][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1ccc(CC(=O)O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CC(=O)O)c(O)c1

Procedure:
A solution of crude 2-(4-methyl-2-phenylmethoxyphenyl)acetonitrile (15 g, 63 mmol) in ethanol (200 ml) and water (50 ml) containing 10 g (0.25 mol) NaOH was heated under reflux overnight, and the ethanol was removed under vacuum. The residue was diluted with water and washed with benzene. The aqueous layer was then acidified with dilute HCl to give an oil which was extracted into ethyl acetate to give (4-methyl-2-phenylmethoxyphenyl)acetic acid (14.2 g, 88%) as an oil which solidified on standing. A solution of this crude (4-methyl-2-phenylmethoxyphenyl)acetic acid in ethanol was hydrogenated over palladium on charcoal to give (2-hydroxy-4-methylphenyl)acetic acid. Anal (C9H10O3) C,H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]#[N:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C[Mg+].[Br-].[CH3:29][CH:30]([CH3:35])[CH2:31][C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH3:16])[C:32](=[O:33])[CH2:31][CH:30]([CH3:35])[CH3:29])[C:12]([C:17]#[N:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: CNc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reactant: CC(C)CC(=O)Cl
Agent: C[Mg+]
Agent: [Br-]
Product: CC(C)CC(=O)N(C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
The product of Step D Example 1 was reacted with MeMgBr followed by 3-methylbutanoyl chloride using the procedure of EXAMPLE 42 Step A to afford the title compound. HPLC/MS: 472.2 (M+1), 474.2 (M+3); Rt=4.43 min.
Reaction SMILES: [CH:1]1([C@@H:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3I)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:46][C:42]4([CH2:45][O:44][CH2:43]4)[CH2:41]3)=[CH:36][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.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>[CH2:45]1[C:42]2([CH2:46][N:40]([C:37]3[CH:38]=[CH:39][C:34]([C:13]4[C:12]5[C:16](=[CH:17][CH:18]=[C:10]([C:8]([NH:7][C@@H:6]([CH:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)[C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=6)=[O:9])[CH:11]=5)[NH:15][N:14]=4)=[CH:35][CH:36]=3)[CH2:41]2)[CH2:43][O:44]1
Reactant: O=C(N[C@H](c1ccccn1)C1CCCC1)c1ccc2[nH]nc(I)c2c1
Reactant: CC1(C)OB(c2ccc(N3CC4(COC4)C3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(N[C@H](c1ccccn1)C1CCCC1)c1ccc2[nH]nc(-c3ccc(N4CC5(COC5)C4)cc3)c2c1
Temperature: 130 °C

Procedure:
The title compound was synthesized according to General Method C2 by utilizing (S)—N-(cyclopentyl(pyridin-2-yl)methyl)-3-iodo-1H-indazole-5-carboxamide (135 mg, 0.30 mmol), 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-6-azaspiro[3.3]heptane (100 mg, 0.33 mmol), Pd(PPh3)4 (36 mg, 0.044 mmol) and 2 M aq Na2CO3 (0.3 mL) in PhMe/EtOH (14 mL, 1:1 mixture). The reaction mixture was heated under microwave irradiation at 130° C. for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with H2O (20 mL), dried (MgSO4) and concentrated under vacuum to give a crude product. Purification by flash chromatography (Biotage Isolera, 50 g HP-SIL, 60-100% EtOAc in hexanes then 0-20% DCM in MeOH) gave the product as a yellow solid. Further purification using reverse phase chromatography (Biotage Isolera, 50 g C18, 10-90% MeCN in H2O) followed by trituration with MeOH gave the title compound as a pale yellow solid (34 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (s, 1H), 8.88 (d, J=8.3 Hz, 1H), 8.34-8.63 (m, 2H), 7.80-7.93 (m, 3H), 7.75 (t, J=6.9 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.24 (t, J=5.3 Hz, 1H), 6.60 (d, J=8.5 Hz, 2H), 4.92 (t, J=9.0 Hz, 1H), 4.74 (s, 4H), 4.05 (s, 4H), 2.53-2.62 (m, 1H), 1.87 (s, 1H), 1.35-1.70 (m, 5H), 1.15-1.35 (m, 2H); MS ESI 494.4 [M+H]+, calcd for [C30H31N5O2+H]+ 494.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([NH:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])=[O:16])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][C:15](=[O:16])[NH:17][CH:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)NC(C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)NC(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-N-(1-phenyl-ethyl)-acetamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]1[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][S:26]([CH2:25][CH2:24][N:15]2[C:14](=[O:13])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:23])(=[O:27])=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CC(NS(=O)(=O)CCN2C(=O)c3ccccc3C2=O)C1

Procedure:
3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonylamino]-azetidine-1-carboxylic acid tert-butyl ester was prepared by an analogous procedure as described for example 1 i) starting from 189 mg (1.1 mmol) 3-amino-azetidine-1-carboxylic acid tert-butyl ester and 300 mg (1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride. The product was obtained in crude form as light yellow foam. Yield: 480 mg MS (ES+): m/e=410.
Reaction SMILES: Cl[CH:2]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4].[CH3:16][NH2:17]>C(O)(C)C>[CH3:16][NH:17][CH:2]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(Cl)c1cncnc1C(F)(F)F
Reactant: CN
Solvent: CC(C)O
Product: CNC(c1cncnc1C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
4.5 g (19 mmol) of 5-(1-chloro-2-methylpropyl)-4-trifluoromethylpyrimidine was dissolved in 50 ml of isopropyl alcohol, and 10 ml (161 mmol) of a 50% methylamine aqueous solution was added, followed by stirring at room temperature for 8 hours. The solvent was distilled off under reduced pressure, and 100 ml of water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 3.4 g (yield: 77%) of 5-(1-(N-methylamino)-2-methylpropyl]-4-trifluoromethylpyrimidine as slightly yellow liquid (refractive index nD20: 1.4529).
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2=[N:16][N:17]([CH2:24][CH2:25][O:26]C)[C:18]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl>[NH2:5][C:6]1[C:15]2=[N:16][N:17]([CH2:24][CH2:25][OH:26])[C:18]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(O)Cc1c2c(nn1CCO)c(N)nc1ccccc12
Reaction time: 4 h
Yield: 24.1 %

Procedure:
Under a nitrogen atmosphere, boron tribromide (6 mL of a 1 M solution in dichloromethane) was added to a solution of 1-[4-amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-ol (0.500 g, 1.59 mmol) in dichloromethane (8 mL), and the reaction was stirred for four hours. The dichloromethane was removed under reduced pressure, and the residue was dissolved in a mixture of ethanol and 3 N hydrochloric acid. A solution of 7 N ammonia in methanol was added, and then the solvent was removed under reduced pressure. The treatment with ammonia and the concentration were repeated two more times. The crude product was purified by chromatography using a HORIZON HPFC system (40+M cartridge, eluting with 0-30% CMA in chloroform) followed by trituration with acetonitrile and recrystallization from acetonitrile to provide 115 mg of 1-[4-amino-2-(2-hydroxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2-methylpropan-2-ol as white crystals, mp 196-198° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[C:4]([O:18][CH3:19])[CH:3]=1.[Cl-].[NH4+]>CO.O.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: COc1cc(F)ccc1Oc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: O
Solvent: CO
Product: COc1cc(F)ccc1Oc1ccccc1N
Temperature: 25 °C
Yield: 100.5 %

Procedure:
To a solution of title compound 90 (9.32 g, 35.4 mmol) in MeOH (30 mL) and water (5 mL) was added ammonium chloride (3.79 g, 70.8 mmol) and zinc chloride (20.83 g, 319 mmol) and the reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and filtered and the solvent removed. The residue was diluted with ethyl acetate and water and the organic phase was washed well with water, dried over Na2SO4, filtered and concentrated to afford title compound 91 (8.3 g, 100%). LRMS (ESI): (calc) 233.09 (found) 234.1 (MH)+.