Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[S:9][C:10]([CH3:18])=[C:11]([CH2:13][C:14](OC)=[O:15])[N:12]=1>C(Cl)Cl>[CH3:18][C:10]1[S:9][C:8]([NH2:7])=[N:12][C:11]=1[CH2:13][C:14]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:15]
Reactant: C1COCCN1
Reactant: COC(=O)Cc1nc(N)sc1C
Solvent: ClCCl
Product: Cc1sc(N)nc1CC(=O)N1CCOCC1
Reaction time: 1 h
Yield: 54 %

Procedure:
A suspension of alumiumchloride (0.86 g, 6.44 mmol) in DCM (50 mL) was treated dropwise with morpholine (4.7 mL, 53.7 mmol) giving a colorless solution. Methyl (2-amino-5-methyl-1,3-thiazol-4-yl)acetate (1.0 g, 5.37 mmol) was added (orange solution) and after 1 h, the reaction mixture was quenched with aqueous citric acid (3%, 10 mL) and basified with saturated aqueous sodium bicarbonate. Extraction with DCM (3×50 mL), drying (sodium sulfate) of the combined organic layers and evaporation of the volatiles gave 0.70 g of a yellow foam. Purification of the solid by flash column chromatography on silicagel eluting with DCM/methanol (10/1 v/v) gave 545 mg (42%) of an ivory solid: Anal. Calcd. (found) for C10H15N3O2S: C, 49.7 (49.5)%; H, 6.3 (6.3)%; N, 17.4 (17.3)%; S, 13.3 (13.3).
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([Br:27])=[CH:10][C:9]=1[CH2:16][CH3:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(OC)cc1CO[Si](C)(C)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cc(Br)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, 24.85 9 (0.0885 mol) of tert-butyl-dimethyl-(2-ethyl-5-methoxy-benzyloxy)-silane (16) and 15.77 g (0.0885 mmol) of NBS were combined in 500 mL of carbon tetrachloride, followed by the addition of 100 g of silica gel 60 (EM Science). The reaction was allowed to stir for 16 hours in the absence of light. The reaction mixture was filtered and the silica gel was washed with dichloromethane. The filtrate was washed with dichloromethane (1×300 mL). The combined organic extracts were washed with 1M NaOH (2×300 mL), dilute NaHSO3 (1×200 mL) and brine (1×200 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to yield crude tert-butyl-dimethyl-(4-bromo-2-ethyl-5-methoxy-benzyloxy)-silane (17). Crude tert-butyl-dimethyl-(4-bromo-2-ethyl-5-methoxy-benzyloxy)-silane (17) was chromatographed on a silica gel column with 20% CHCl3 in hexane to afford 19.70 g (62%) of tert-butyl-dimethyl-(4-bromo-2-ethyl-5-methoxy-benzyloxy)-silane (17).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=O)=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:44][C@H:45]([C:53]([OH:55])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:1]([O:18][CH:19]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([NH:44][C@H:45]([C:53]([OH:55])=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:28])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 86.9 %

Procedure:
Starting from N-(3-hexadecanoyloxyoctadecanoyl)-β-alanine (1.52 g) prepared by the method of Example 31 and L-phenylalanine (1.65 g), N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-phenylalanine (1.64 g) was obtained as crystals according to a similar manner to that of Example 29.
Reaction SMILES: N[C:2]1([CH2:24][CH3:25])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:20]3[C:19]4[C@@H:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16][C:15]=4[S:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[CH2:26]=O.[BH3-][C:29]#[N:30].[Na+]>CO.O>[CH3:26][N:30]([CH3:29])[C:2]1([CH2:24][CH3:25])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:20]3[C:19]4[C@@H:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16][C:15]=4[S:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1
Reactant: C=O
Reactant: CCC1(N)CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC1(N(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 10-mL round-bottom flask placed a solution of 2-[(3R)-12-[(4-amino-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (120 mg, 0.33 mmol, 1.00 equiv) in 5 mL of methanol was added HCHO (37%, 1 mL) and the reaction was stirred at room temperature for 30 min. Then NaBH3CN (83 mg, 1.32 mmol, 3.97 equiv) was added to the reaction mixture and stirred for 8 hr at room temperature. After completion, the reaction mixture was diluted with water and extracted with DCM. After concentration in vacuo, The crude product (120 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 50 mM NH4HCO3 and CH3CN (6.0% CH3CN up to 52.0% in 14 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[(3R)-12-[[4-(dimethylamino)-4-ethylcyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (41.4 mg) as a white semi-solid. MS (ES): m/z 390 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.47 (s, 1H), 5.44-5.46 (m, 1H), 3.64-3.69 (m, 2H), 3.32-3.33 (m, 1H), 3.10-3.12 (m, 1H), 2.99-3.02 (m, 1H), 2.68 (m, 1H), 2.09-2.39 (m, 10H), 1.61-1.86 (m, 9H), 0.93-0.96 (t, 3H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[C:1]([O:10][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCCCCCO
Reactant: C=CCCCCCC(=O)O
Product: C=CCCCCCCCCOC(=O)CCCCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from oct-7-enoic acid and dec-9-en-1-ol. The resulting yellow oil was purified by silica gel chromatography (50:1 hexanes: diethyl ether) to afford the desired product as a colorless oil. IR (neat): 3077 (m), 2926 (s), 2855 (s), 1736 (s), 1641 (m), 1462 (m), 1417 (m), 1351 (m), 1255 (s), 1168 (s), 1113 (m), 1076 (m), 993 (s), 909 (s), 734 (m), 632 (m); 1H NMR (400 MHz, CDCl3): δ 5.86-5.75 (2H, m), 5.02-4.91 (4H, m), 4.05 (2H, t, J=6.8 Hz), 2.29 (2H, t, J=7.6 Hz), 2.08-2.01 (4H, m), 1.67-1.59 (4H, m), 1.42-1.27 (14H, m); 13C NMR (100 MHz, CDCl3): δ 174.0, 139.2, 138.9, 114.5, 114.3, 64.5, 34.4, 33.9, 33.7, 29.5, 29.3, 29.1, 29.0, 28.8, 28.7, 28.6, 26.0, 25.0; HRMS (ESI+) [M+H]+ calcd for C18H33O2: 281.2481. found: 281.2475.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:33]=[CH:34][CH:35]=1)[CH2:12][N:13]1[CH2:17][C:16](=[O:18])[N:15]([C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]3[C:26]([CH3:31])=[N:27][O:28][C:29]=3[CH3:30])[CH:23]=2)[C:14]1=[O:32])(C(C)(C)C)(C)C.Cl>CO>[CH3:31][C:26]1[C:25]([CH2:24][N:22]2[CH:23]=[C:19]([N:15]3[C:16](=[O:18])[CH2:17][N:13]([CH2:12][C:11]4[CH:33]=[CH:34][CH:35]=[C:9]([OH:8])[CH:10]=4)[C:14]3=[O:32])[CH:20]=[N:21]2)=[C:29]([CH3:30])[O:28][N:27]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)C2=O)cn1
Agent: Cl
Solvent: CO
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(O)c3)C2=O)cn1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
1-(3-(tert-butyldimethylsilyloxy)benzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (Example 10-10b) (6.00 g, 12.11 mmol) was dissolved in methanol (100 mL) and treated with HCl (2.0 M solution in diethyl ether, 5 equivalents). The solution was refluxed for 2. The mixture was allowed to cool down to room temperature and the solvent was removed. The residue was triturated in toluene, filtered and recristallized from ethanol at 4° C. to give 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)imidazolidine-2,4-dione (4.50 g, 11.80 mmol, 97%) as a white solid. 1H NMR (DMSO, 400 MHz): δ 2.15 (s, 3H), 2.39 (s, 3H), 3.97 (s, 2H), 4.43 (s, 2H), 5.18 (s, 2H), 6.68 (m, 3H), 7.12 (m, 1H), 7.80 (s, 1H), 8.17 (s, H), 9.41 (s, H). MS 382 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>O1CCCC1.O>[C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)O)C2C(=O)OC(C)(C)C)cc1
Reaction time: 0.75 h

Procedure:
1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (6g, 12 mmol) is dissolved in a mixture of 120 ml Tetrahydrofuran and 78 ml Water. LiOH.H2O (1 g, 24 mmol) is added. After 45 min., more Water (15 ml) is added and the reaction solution is stirred at room temp. for 24 h. The solvent is evaporated and the remaining solid is resolved in Water/Diethylether. The water layer is acidified to pH 1. The organic phase is separated and the water phase is extracted twice with Ethylacetate. The combined organic fractions are dried with MgSO4 and filtered. The solvent is evaporated to afford the product: Cal. 412.5, found (M)+412.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1>>[CH:10]1([NH:16][C:6]2[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCC1
Reactant: c1ccc2[nH]ncc2c1
Reactant: Cc1cc(Cl)nc(Cl)n1
Product: Cc1cc(NC2CCCCC2)nc(-n2ncc3ccccc32)n1

Procedure:
Was prepared according to Method A from 2,4-dichloro-6-methylpyrimidine, cyclohexylamine and indazole. LC-ESI-HRMS of [M+H]+ shows 308.1859 Da. Calc. 308.18752 Da, dev. −5.3 ppm.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19].[H-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)=CCBr
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CCN(c1ccc(I)cc1)c1ncccn1
Yield: 94.9 %

Procedure:
In the same manner as in Reference Example 13, N-(4-iodophenyl)pyrimidin-2-amine (150 mg) and 1-bromo-3-methylbut-2-ene (90 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-N-(3-methyl-2-butenyl)pyrimidin-2-amine (175 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]cc(CCC(=O)O)c1C
Yield: 42.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (190 mg), 163 mg of 6-methoxy-2-oxindole, and 2 drops of piperidine in 2 mL of ethanol were heated to 90° C. for 3 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 140 mg of the title compound (43%) as a brown solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([C:26]3[CH:31]=[CH:30][C:29](Cl)=[CH:28][CH:27]=3)[OH:25])=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C(=O)C1C=CC=CC=1>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Cl)ncc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccccc3)c(Cl)ncc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (See Compound 49, step 3, 1.15 mg, 3.0 mmol) in THF (30 mL) at −78° C. was added LDA (2M in THF, 6 mL, 12 mmol) dropwise. The reaction was stirred at −78° C. for 30 min then benzaldehyde (636 mg, 6.0 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at −78° C. for 20 min, quenched with aq. NH4Cl (5 mL) then diluted with EA (30 mL) and water (8 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated to a residue which was purified by chromatography eluted with PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-(hydroxy(phenyl)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H, 3H)-dione (450 mg, 30.7% yield) as a colorless oil. LCMS: [M+-OH] 472 and TR=2.058 min.
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[OH:39].[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4OC5C=CC=C(C)C=5N=4)=[CH:52][CH:51]=3)[C:42]=12>>[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:74][CH2:75][N:76]([CH3:79])[CH2:77][CH2:78]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[O:39][C:33]5[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:32]=5[N:31]=4)=[CH:52][CH:51]=3)[C:42]=12
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Reactant: Nc1cc(Cl)ccc1O
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6cc(Cl)ccc6o5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-chloro-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.246 mmol) and 2-amino-4-chlorophenol (0.035 g, 0.246 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine. The compound was formed as a pale yellow solid (0.020 g, 15%):
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: CNOC
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
100.0 g (0.447 mol) 3-bromobenzoyl chloride was added to an ice cooled solution of 48.9 g (0.491 mol) N,O-dimethylhydroxylamine hydrochloride and 140.0 ml (1.00 mol) triethylamine in 650 ml dry dichloromethane over a period of 30 minutes. After additional stirring for 30 minutes, 370 ml water was added and the organic layer dried over sodium sulfate. Fractionated distillation in vacuo yielded 101.4 g (93%) B1, b.p. 114-129° C./0.07 mbar, as a colorless oil.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(O)CC[N+]([F:20])(CC2)C1.[CH3:21][O:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH2:28][C:29]2=[O:32])=[CH:25][CH:24]=1>C(#N)C>[F:20][C:31]1[C:23]([O:22][CH3:21])=[CH:24][CH:25]=[C:26]2[C:30]=1[C:29](=[O:32])[CH2:28][CH2:27]2
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: O[N+]12CC[N+](F)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1ccc2c(c1F)C(=O)CC2

Procedure:
A solution of Accufluor™ fluorinating reagent (6.75 g, 9.00 mmol) and 6-methoxy-indan-1-one (500 mg, 3.00 mmol) in ACN (600 mL) was heated at 80° C. for six hours. The reaction was concentrated under reduced pressure, and the residue was purified by medium pressure chromatography (silica, 10 to 25% EtOAc:hexanes) to yield 38.1. 1H NMR (400 MHz, CDCl3) δ ppm 7.21-7.29 (m, 1H), 7.12-7.18 (m, 1H), 3.92 (s, 3H), 3.04-3.12 (m, 2H), 2.70-2.76 (m, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:14][N:15]([CH3:16])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C=O)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A suspension of 4-fluoro-2-trifluoromethylbenzaldehyde (500 mg, 2.60 mmol), dimethylamine (5.5 mol/L in ethanol, 0.95 mL, 5.2 mmol), potassium carbonate (360 mg, 2.6 mmol) in 5.2 mL of N,N-dimethylformamide was stirred at 110° C. overnight in a sealed tube. After the reaction mixture was diluted with water, the solution was extracted with ether. The extract was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 75/25) to obtain the title compound as a pale yellow powder (393 mg, 70%).
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:7]3=[CH:6][C:5]=2[C:4](=[O:21])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[F:38]>CN(C=O)C.CC#N>[F:38][C:30]1[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:29]=1[O:21][C:4]1[C:5]2[CH:6]=[C:7]3[O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][C:8]3=[CH:9][C:10]=2[N:1]=[CH:2][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=c1cc[nH]c2cc3c(cc12)OCCOCCOCCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc4c(cc23)OCCOCCOCCO4)c(F)c1
Yield: 39.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 7,8,10,11,13,14-Hexahydro-1H-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalen-4-one (12.2 g, 43.3 mmol, 1.0 eq.), acetonitrile (150 ml), DMF (150 ml) and cesium carbonate (28.2 g, 86.5 mmol, 2.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 1,2-difluoro-4-nitro-benzene (7.57 g, 47.6 mmoL, 1.1 eq) was added over a 10 minute period. After 2 hours the reaction was complete at which time 75% of the MeCN and DMF were removed and the resulting solution was poured over into ice water. The solid was filtered and dried and further columned with a biotage system. The eluent was 1:3 ethyl acetate/hexane. Removal of the solvent afforded 4-(2-Fluoro-4-nitro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclodo-deca[b]naphthalene as a pale green solid (7.4 g, 41% yield). 1HNMR (400 MHz, DMSO): 8.58 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.04 (t, 1H), 6.88 (m, 1H), 6.50 (m, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+431.4. found 431.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:17])[C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]2)=[O:21].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:17])[C:10](=[O:16])[CH:11]([CH2:19][C:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]2)=[O:21])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Reactant: COC(=O)CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
At RT, a solution of (R)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (603) (5.38 g, 21.95 mmol) in 20 mL of THF and 20 mL of DMF was treated with 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (5.44 g, 16.18 mmol) and K2CO3 (5.59 g, 40.4 mmol) and stirred at RT for 6 h. It was diluted with 250 mL of EtOAc, filtered through a flitted funnel, rinsed with 2×15 mL of EtOAc. The filtrate was washed with sat NH4Cl (2×25 mL) followed by brine (15 mL). The organic solution was dried over Na2SO4 and concentrated. The residue was passed through a short column (35-75% EtOAc in hexanes) to get rid of the solvent front peaks and the base line peaks. Fractions with m/z (ESI, +ve) 501.2 (M+H)1 were collected and concentrated to give methyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (326a) as a brown residue. To the brown residue in a glass tube in 25 mL of EtOH and 10 mL of HOAc was added NH4OAc (8.46 g, 110 mmol). The tube was sealed and heated in an oil bath at 50° C. for 8 h. The mixture was concentrated to half of its volume, diluted with 250 mL of EtOAc, washed sequentially with 15 mL of water, 15 mL of 1 N NaOH and 5 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (eluted with a gradient of 35-65% EtOAc in hexanes) to give methyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (326b) (6.3 g, 71% yield) as a yellow amorphous. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (1H, br.), 7.76 (1H, dd, J=7.4, 1.2 Hz), 7.63 (1H, dd, J=8.0, 1.2 Hz), 7.38 (2H, m), 7.03 (1H, d, J=7.8 Hz), 5.94 (1H, s), 5.44 (1H, m), 3.77 (3H, s), 2.56 (3H, s), 1.58 (9H, s), 1.40 (12H, m). m/z (ESI, +ve) 482.1 (M+H)+.