Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[C:6](/[N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)=[CH:7]\[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1>[CH:1]1([C@@H:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)/C=C(\C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: [H][H]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 35 °C
Reaction time: 22 h

Procedure:
(R)-Methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilypethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoate ((R)-22). A solution of (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 815 mg) in tetrahydrofuran (THF, 8.0 mL) in a pressure glass tube was treated with the catalyst [Rh(COD)(−)-DuanPhos](BF4) (4.6 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 50 bar pressure. The reaction mixture was stirred at 35° C. under this hydrogen pressure for 22 h. When HPLC analysis showed that the substrate was almost completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 94.7% ee (97.35% of the second peak, (R)-22; 2.65% of the first peak, (S)-22) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with tetrahydrofuran (THF, 5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (778 mg) was analyzed by chiral HPLC analysis and result showed a 94.7% of enantiomeric excess favoring the second peak (97.35% of the second peak, (R)-22; 2.65% of the first peak, (S)-22).
Reaction SMILES: [CH:1]([N:3]1[CH:7]([C:8]([OH:10])=O)[CH2:6][S:5][CH:4]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:2].Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH2:24][S:25][CH3:26])[NH2:22].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.CN(C)C=O>[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH2:24][S:25][CH3:26])[NH:22][C:8]([CH:7]1[CH2:6][S:5][CH:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]1[CH:1]=[O:2])=[O:10]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=CN1C(C(=O)O)CSC1c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCSC)NC(=O)C1CSC(c2cccnc2)N1C=O
Reaction time: 1 h
Yield: 39190.2 %

Procedure:
To a solution of 1.3 g of N-formyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid in 50 ml of tetrahydrofuran plus 10 ml of N,N-dimethylformamide, there were added, at 4° C. or below, 1.16 g of L-methionine methyl ester hydrochloride, 1.17 g of 1-hydroxybenzotriazole, 560 mg of N-methylmorpholine and 1.32 g of dicyclohexylcarbodiimide, in that order. The mixture was stirred at 4° C. or below for 1 hour and then at room temperature for 1 hour. The reaction mixture was then treated in the same manner as in Example 1. Purification by silica gel column chromatography [eluent: chloroform-methanol (9:1)] gave 820 g of [N-formyl-2-(3-pyridyl)thiazolidine-4-carbonyl]-L-methionine methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7].[C:15](=S)=[S:16]>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH:6]1[N:8]=[N:9][C:15](=[S:16])[O:7]1
Reactant: S=C=S
Reactant: NNC(=O)COc1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: S=C1N=NC(COc2ccc(Cl)cc2Cl)O1

Procedure:
Following the procedure of Example IIA, 2,4-dichlorophenoxyacetic acid hydrazide (23.5 g) and carbon disulfide (38 g) in DMF (50 ml) were reacted and worked up to yield 2-(2,4-dichlorophenoxymethyl)-1,3,4-oxadiazol-5-thione (IIIA).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:24][NH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:15]=3[C:16]([N:25]([CH3:24])[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: CNCCc1ccccc1
Product: CN(CCc1ccccc1)C(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid was coupled with N-methylphenethylamine as in EXAMPLE 1, Part C. HPLC: RT=9.90 min. MS (ESI−): mass calcd. for C22H19BrN4O3S2, 530.01; m/z found, 529/531 [M−H]−. 1H NMR (400 MHz, CDCl3; rotameric broadening): 8.95-8.80 (br s, 0.6H), 8.57-8.43 (br s, 0.4H), 8.27 (dd, J=7.0, 0.9, 1H), 8.23 (br d, J=8.8, 1H), 7.80-7.64 (m, 2H), 7.37-6.85 (br m, 6H), 6.73-6.62 (br m, 0.6H), 6.55-6.40 (br m, 0.4H), 3.68-3.35 (br m, 1.3H), 3.35-3.07 (br m, 0.7H), 3.07-2.25 (br m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=O)[CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCc1ccccc1)NC1CCN(c2ccc(OCc3ccccc3)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1ccc(CCCCNC2CCN(c3ccc(OCc4ccccc4)cc3)CC2)cc1
Yield: 17.2 %

Procedure:
Following the procedure of example 40b, N-[1-(4-benzyloxy-phenyl)-piperidin-4-yl]-4-phenyl-butyramide (450 mg) was reduced with LiAlH4 to give [1-(4-benzyloxy-phenyl)-piperidin-4-yl]-(4-phenyl-butyl)-amine (75 mg; 17%) as a light yellow solid (MS: m/e=415.4 (M+H+)).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:32])([OH:31])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].O>CN(C=O)C>[CH3:32][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[O:31][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCC(OCc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CCC(OCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
(S)-1-(2-Chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylbenzyloxy)piperidin-1-yl]propan-2-ol prepared in Example 254 (1.36 g, 2.8 mmol) was dissolved in DMF (15 ml). To the solution, sodium hydride (134 mg, 3.36 mmol) was added with cooling on ice-bath followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and crystallized from methylene chloride-diisopropyl ether to afford (S)-2-methyl-6-nitro-2-[4-(4-trifluoromethylbenzyloxy)piperidin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (431 mg, yield 44%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:37](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:37][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:27][CH:26]=3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CNc5ccc(N6CCCCC6)cc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNc5ccc(N6CCCCC6)cc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 23.3 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-piperid-1-ylphenyl)amine is prepared as described in Example 179a starting with 0.09 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-piperid-1-ylphenyl)amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.55 cm3 of 5N potassium hydroxide. 0.016 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-piperid-1-ylphenyl)amine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10]N2[C:4](=NCCC2)[CH2:3][CH2:2]1.[CH3:12][C:13](=[O:17])[O:14][CH2:15][CH3:16]>C(#N)C>[C:1]1([C:12]2[C:13](=[O:17])[O:14][CH2:15][C:16]=2[C:4]2[CH:3]=[CH:2][CH:1]=[CH:11][CH:10]=2)[CH:11]=[CH:10][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(C)=O
Solvent: CC#N
Product: O=C1OCC(c2ccccc2)=C1c1ccccc1
Reaction time: 0.5 h

Procedure:
After dissolving compound 2 (5.00 g, 36.7 mmol) in ACN (30 ml), compound 10 (7.31 g, 36.7 mmol) and TEA (5.63 ml) were sequentially added thereto. After the agitation for 30 minutes at room temperature, the temperature was reduced to 0° C., DBU (16.5 ml) was dropped and the agitation for 1 hour was carried out. After the termination of the reaction, EA and 1N HCL aqueous solution were added thereto and the organic layer was washed three times with brine. Water was removed by using anhydrous Na2SO4 and the distillation under the reduced pressure was carried out to obtain compound 18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1.[N:34]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])([CH3:46])[C@H:35]([C:43](O)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1COCC1.C(N=C=NC(C)C)(C)C>O>[C:50]([O:49][C:47](=[O:48])[N:34]([C@@H:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:43]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:33])=[N:9][N:10]([CH2:30][CH2:31][OH:32])[CH:11]=2)=[CH:20][CH:19]=1)=[O:44])[CH3:46])([CH3:53])([CH3:51])[CH3:52]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a mixture of compound 5A (6.50 g, 13.98 mmol) and BOC-N-Me-Phe-OH (6A, 9.76 g, 34.94 mmol) was added anhydrous THF (350 mL) and the resultant mixture was stirred at rt for 10 min. Diisopropylcarbodiimide (DIPC, 5.41 mL, 34.94 mmol) was added slowly at rt. The reaction mixture was stirred at rt overnight. Water (˜10 mL) was added to the above mixture and the reaction mixture was stirred at rt for 3 hour. Solvent was removed and the residua were dissolved in ethyl acetate. It was filtered to remove solid (diisopropylurea). The filtrate was purified by silica column chromatography eluting with hexanes-ethyl acetate (v/v 1/1, 2/3, 1/2) to provide the title compound (7A, 4.3 g) as foam-like powder in 42.3% yield. 1H NMR (CDCl3, 500 MHz) δ 10.63 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 7.76 (s, 1H), 7.63 (m, 1H), 7.52 (d, 2H, J=7.5 Hz), 7.40-7.10 (m, 7H), 6.96 (d, 1H, J=8.0 Hz), 5.35 (br s, 1H), 5.13 (m, 1H), 4.29 (s, 2H), 4.05 (s, 2H), 3.81 (m, 1H), 3.20 (t, 1H, J=8.0 Hz), 3.09 (m, 2H), 2.94 (s, 3H), 2.87 (m, 1H), 2.35 (m, 1H), 1.75-1.10 (m, 12H), 0.74 (m, 1H). LCMS (ESI) m/z 748.26 (MNa+), 726.27 (MH+), 670.21, 626.20, 465.10, 373.18, 317.14 (100). HPLC: tR=5.70 min.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH2:20]([O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:27]([O:36][CH2:37][CH3:38])=[CH:26][C:24]=1[NH2:25])[CH3:21]>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:25][C:24]2[CH:26]=[C:27]([O:36][CH2:37][CH3:38])[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:29][C:23]=2[O:22][CH2:20][CH3:21])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCOc1cc(N2CCOCC2)c(OCC)cc1N
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(Nc2cc(OCC)c(N3CCOCC3)cc2OCC)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2,5-diethoxy-4-morpholin-4-ylaniline in a similar manner as described for e.g. Examples 6-9, 22-25, 28 and 32-35. 1H NMR (400 MHz, CD3CN): δ 7.46 (bs, 1H), 7.27-7.22 (m, 1H), 7.18-7.09 (m, 4H), 6.25 (d, 2H), 3.86-3.80 (m, 2H), 3.76-3.70 (m, 6H), 3.53-3.47 (m, 2H), 2.91-2.87 (m, 4H), 1.85-1.77 (m, 2H), 1.52-1.42 (m, 2H), 1.36 (t, 3H), 1.22 (t, 3H), 0.99 (t, 3H); Mass Spectrum: M+H+ 530.
Reaction SMILES: ClC1C=CC(C[N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11](C)[C:10]=3[N:9]=[C:8]2OC2C=CC=C(OC(F)(F)F)C=2)=CC=1.C(=O)([O-])[O-].[K+].[K+].BrCCCO[Si](C(C)(C)C)(C)C>CN(C=O)C.O>[NH:13]1[C:14](=[O:16])[C:15]2[NH:7][CH:8]=[N:9][C:10]=2[NH:11][C:12]1=[O:17]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Temperature: 100 °C

Procedure:
Step 1 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-2,6(3H,7H)-dione (3.73 g, 7.99 mmol, intermediate 9) and potassium carbonate (1.66 g, 11.99 mmol) were combined in DMF (56 mL) and (3-bromopropoxy)(tert-butyl)dimethylsilane (2.43 g, 9.59 mmol) was added. The reaction was heated at 100° C. After heating for 3 h the reaction was cooled, diluted with water (200 mL) and extracted with ethyl acetate (3×200 ml). The combined extracts were washed with 1N lithium chloride (2×100 mL), dried with magnesium sulfate and evaporated under reduced pressure to provide 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (5.7 g crude) as a light golden oil. LCMS retention time=5.646 and 98% purity, LCMS MH+ 639.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)=[N:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.[Br:27]Br>C(O)(=O)C>[Br:27][C:21]1[CH:22]=[N:23][C:24]2[C:19]([CH:20]=1)=[CH:18][C:17]([S:16][C:13]1[N:11]3[N:12]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:8]=[CH:9][C:10]3=[N:15][N:14]=1)=[CH:26][CH:25]=2
Reactant: BrBr
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc5ncccc5c4)n3n2)cn1
Solvent: CC(=O)O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(Br)cc5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.2 %

Procedure:
To a solution of 6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-quinoline (1 g, 2.785 mmol) in glacial acetic acid (20 mL) was added bromine (0.716 mL, 13.93 mmol) dropwise. The reaction mixture was stirred at room temperature for 5 min then at 100° C. for 3 h. The reaction was cooled to room temperature, and the mixture was concentrated in vacuo. The residue was partitioned between 10% aqueous NaOH and 10% methanol/di-chloromethane. The organic layer was separated, washed with 1 M aqueous Na2S2O3, dried over sodium sulfate, filtered, and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-7% methanol/dichloromethane afforded 381 mg of 3-bromo-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-quinoline as a beige solid (31% yield): 1H NMR (DMSO-d6): δ 3.89 (s, 3H), 7.77 (dd, 1H), 7.80 (d, 1H), 7.99 (d, 1H), 8.00 (s, 1H), 8.43 (s, 1H), 8.48 (d, 1H), 8.68 (d, 1H), 8.92 (d, 1H); MS (m/z) 438, 440 [M+H+]+.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].N12CCC(CC1)CN2.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([NH2:23])(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([N:23]=[C:2]=[O:3])(=[O:22])=[O:21]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NS(=O)(=O)c1ccco1
Agent: C1CN2CCC1CN2
Solvent: Cc1ccccc1
Product: O=C=NS(=O)(=O)c1ccco1
Reaction time: 2 h

Procedure:
Dry toluene (150 ml), 25 ml oxalyl chloride (295), and a trace of DABCO (diaza-bicyclo[2.2.2]octane) were heated to 90°. Ten g of 2-furansulfonamide was added over a 15 minute period and the mixture was held at 95° for 2 hours. After filtering, the solvent was removed under vacuum to yield 2.1 g of an oil showing the characteristic isocyanate absorption in the infrared (2280 cm-1).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:27]=1)[C:18]1[C:17]([Br:19])=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[Br:19][C:17]1[C:18]2[C@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:27]3)[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:7]=3)[O:12][C:13]=2[CH:14]=[CH:15][C:16]=1[O:20][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)CI
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ccc(O)c(Br)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc2c(c1Br)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A vial was charged with (S)-2-amino-1′-bromo-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (163 mg, 0.384 mmol), cesium carbonate (375 mg, 1.152 mmol), and DMF (2.0 mL). The mixture was stirred for 10 min, then 1-iodo-2,2-dimethylpropane (102 μL, 0.768 mmol) was added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 2 h at 110° C. LCMS at this time shows no starting material and mainly desired product. The mixture was partitioned between water and EtOAc. Brine was added to break up the emulsion that formed and this was partially successful. The aqueous layer was extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 50-g SNAP column, eluting with 0-70% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-1′-bromo-2′-(neopentyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid after evaporation from DCM/hexane.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=O.[CH2:9]([NH2:12])[CH:10]=[CH2:11].[BH4-].[Na+]>C(O)C>[CH2:9]([NH:12][CH:4]([CH3:6])[CH:3]([O:7][CH3:8])[O:2][CH3:1])[CH:10]=[CH2:11]
Reactant: C=CCN
Reactant: COC(OC)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCNC(C)C(OC)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
20 g of molecular sieve are added to 12 g (0.1 mol) of 1,1-dimethoxyacetone in 100 ml of ethanol, and 7 g (0. 12 mol) of allylamine are then added dropwise. The mixture is allowed to stand overnight at room temperature, the liquid phase is decanted off from the molecular sieve and cooled to 0° C. in an ice-bath, and 4 g (0.1 mol) of sodium borohydride are added in small portions. The mixture is stirred overnight at room temperature, concentrated and taken up in 100 ml of water, and this mixture is saturated with potassium carbonate and extracted five times using 100 ml portions of chloroform. The extracts are dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[N:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:41][S:38]([C:35]3[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=3)(=[O:40])=[O:39])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1ccncc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccncc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-pyridinesulfonamide (J. Chem. Soc., 1958, 3514: 1H-NMR (CDCl3) δ 8.81 (2H, d, J=5.4 Hz), 7.77 (2H, d, J=5.9 Hz), 7.46-7.18 (9H, m), 6.11 (1H, br.s), 3.44-3.41 (2H, m), 2.84-2.79 (2H, m), 2.31 (3H, s), 2.21 (3H, s).
Reaction SMILES: [CH2:1]([N:6]1[C:15]2[C:10](=[N:11][C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=2)[CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].[C:28]([O:33][CH3:34])(=[O:32])[CH2:29]C=C>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:22]1([C:12]2[N:11]=[C:10]3[CH2:9][CH2:8][CH2:7][N:6]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:29][C:28]([O:33][CH3:34])=[O:32])[C:15]3=[N:14][C:13]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CCC(=O)OC
Reactant: C=CCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COC(=O)C/C=C/CCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(pent-4-enyl)-2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (step 1) (200 mg, 0.563 mmol) and methyl but-3-enoate (225 mg, 2.251 mmol) in DCM (300 ml) was added Grubbs Catalyst second generation (5 mol %, 23.88 mg, 0.028 mmol). The reaction was stirred at RT under an atmosphere of nitrogen overnight. An additional portion of Grubbs Catalyst second generation (5 mol %, 23.88 mg, 0.028 mmol) was added and stirring continued for 2.5 h. The solvent was removed in vacuo and the resulting crude was purified by chromatography on silica eluting with EtOAc/iso-hexane to afford the title compound;