Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[N:10]2[CH3:22])=[CH:5][C:4]=1[S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26]>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:22])[C:11](=[N:14][C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:24](=[O:29])(=[O:28])[N:25]([CH3:26])[CH3:27]
Reactant: CN1C(=Nc2ccc(O)cc2)SCC1(O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Agent: Br
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccc(O)cc3)n2C)ccc1Cl
Temperature: 25 °C

Procedure:
5.23 g (0.01 mole) of 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-(4-hydroxyphenylimino)-thiazolidin-4-ol hydrobromide in 70 ml of glacial acetic acid are heated in the course of 20 min. to boiling. After cooling, the crystallization is completed by addition of about 150 ml of diisopropyl ether, the mixture is stirred for a further hour at room temperature and filtered. Colorless crystals, m.p. 275°-279° C. (decomp.).
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19]C[C:17](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.NC1C=CC(C2CCCC(CC(OCC)=O)C2)=CC=1.[Br:46]C1C=CC([C@@H]2CCC(=O)C2)=CC=1>>[Br:46][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:20][CH2:19][C:17](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16]2)=[CH:13][CH:14]=1
Reactant: O=C1CC[C@@H](c2ccc(Br)cc2)C1
Reactant: CCOC(=O)C=C1CCCC(c2ccc(OCc3ccccc3)cc2)C1
Agent: CCOC(=O)CC1CCCC(c2ccc(N)cc2)C1
Product: CCOC(=O)C=C1CC[C@@H](c2ccc(Br)cc2)C1

Procedure:
Following the general procedure described for ethyl {3-[4-(benzyloxy)phenyl]cyclohexylidene}acetate (Intermediate 89 (ii)), replacing 3-[4-(benzyloxy)phenyl]cyclohexanone with (3R)-3-(4-bromophenyl)cyclopentanone the title compound was obtained; 1H NMR δ1.18-1.23 (3H, m), 1.61-1.78 (1H, m), 2.06-2.20 (1H, m), 2.53-2.67 (3H, m), 2.84-3.04 (1H, m), 3.08-3.24 (1H, m), 4.01-4.10 (2H, m), 5.82-5.85 (1H, m), 7.24-7.28 (2H, m), 7.47-7.51 (2H, m); MS m/e MH+ 310.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[N:4]([CH2:12][CH:13]=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:13][CH2:12][N:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:11]=[C:2]([CH3:1])[C:3]4=[O:15])[CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: Cc1cc2ccccc2n(CC=O)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc2ccccc2n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
To 25 mL of a chloroform solution containing 341 mg of (3-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 498 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 80 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 480 mg of sodium triacetoxyborohydride was added, and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1], to give 126 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[F:35])#[N:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[C:27]([F:35])[CH:28]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1F
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(C#N)c(F)c4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-cyano-3-fluoro-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 4): tR=1.84 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:17][CH2:16][C:10]3([CH2:14][NH:13][C:12](=[O:15])[CH2:11]3)[CH2:9][CH2:8]2)[CH:6]=1.[H-].[Na+].[CH3:20]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:17][CH2:16][C:10]3([CH2:14][N:13]([CH3:20])[C:12](=[O:15])[CH2:11]3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: O=C1CC2(CCC(n3cc(Br)cn3)CC2)CN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC2(CCC(n3cc(Br)cn3)CC2)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro[4.5]decan-3-one (mixture of intermediate 30 and 31 obtained in step 5; 4 g, 13.4 mmol) in DMF (10 mL) was added sodium hydride (60%) (0.8 g, 0.0116 mol) followed by methyl iodide (2.2 mL, 14.8 mmol) at 0° C. The reaction mixture was slowly allowed to warm to RT and stirred for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic phases were washed with water (50 mL) and brine (50 mL), dried over sodium sulphate, filtered and concentrated. Purification by flash chromatography on silica (Pet. ether: ethyl acetate) afforded the title compound (mixture of two isomers) as an off white solid (1.8 g, 43%). 1H NMR (400 MHz, DMSO-d6) δ 8.04-8.03 (m, 1H), 7.51-7.50 (m, 1H), 4.16-4.10 (m, 1H), 3.24 (s, 1H), 3.09 (s, 1H), 2.70-2.69 (m, 3H), 2.21 (s, 1H), 2.09 (s, 1H), 1.90-1.86 (m, 6H), 1.79-1.54 (m, 2H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:30][O:31][CH2:32][CH2:33]I>CN(C=O)C.O1CCOCC1>[C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:33][CH2:32][O:31][CH3:30])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COCCI
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)[C@@H]1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3.17 g (9.86 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl]dihydrofuran-2-(3H)-one in 190 ml of DMF/dioxane, 1: 1, are treated, under an N2 atmosphere, with 6.4 g (19.7 mmol) of Cs2CO3 and 2.0 g (9.86 mmol) of 2-methoxyethyl iodide. Since HPLC indicates that uureacted 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl]-dihydrofuran-2-(3H)-one is still present after 18 h at RT, a further 1.2 g of 2-methoxyethyl iodide are added in portions. As soon as HPLC indicates that the reaction is complete, the reaction mixture is poured onto 190 ml of ice-water, and the whole is extracted 3× with methylene chloride. The organic phases are washed with water and saline, dried with Na2SO4 and evaporated. Stirring up the residue with hexane in an ultrasonication bath affords the title compound: TLC Rf (D)=0.08; FAB-MS (M+H)+ =380.
Reaction SMILES: C([O:4][C:5](=[O:66])[C@@H:6]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:7][C:8]1[CH:57]=[CH:56][C:11]([O:12][C:13]([NH:15][C@H:16]([C:28]([NH:30][C@H:31]([C:53]([NH2:55])=[O:54])[CH2:32][S:33][C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:29])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:10][CH:9]=1)C=C.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[C:24]([O:23][C:21]([NH:20][CH2:19][CH2:18][CH2:17][C@@H:16]([C:28]([NH:30][C@H:31]([C:53]([NH2:55])=[O:54])[CH2:32][S:33][C:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:29])[NH:15][C:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:6]([NH:58][C:59]([O:61][C:62]([CH3:63])([CH3:65])[CH3:64])=[O:60])[C:5]([OH:66])=[O:4])=[CH:57][CH:56]=1)=[O:14])=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Temperature: 25 °C

Procedure:
5.27 g (5.65 mmol) of the compound from example 12A was dissolved in approx. 60 ml tetrahydrofuran. 2.1 ml (15.2 mmol) Triethylamine, 0.57 ml (15.2 mmol) formic acid and 0.35 g (0.30 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 60 ml water and twice extracted with approx. 50 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 500 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 20/1 and dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. The raw product was further purified by preparative RP-HPLC on a C18 column with a water/methanol gradient to yield 1.37 g (24% of theory) product.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N+:15]([O-])=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].P(Cl)(Cl)([Cl:38])=O>C(OCC)(=O)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([Cl:38])[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26]
Reactant: O=C1c2c(-c3ccccc3)cc[n+]([O-])c2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
5-[3,5-Bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine 10-oxide (compound of Reference Example 10; 400 mg) was added to phosphorus oxychloride (1.5 mL), and the mixture was refluxed for 1 hour while heated. The solvent was removed by distillation to obtain a residue. To this residue, ethyl acetate was added, and then the resulting crystals were collected. As a result, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine was obtained (440 mg, 99%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:4][O:3]1.[C:5]([O:9][C:10]([N:12]([C:20]1[C:25]([CH3:27])([CH3:26])[S:24](=[O:29])(=[O:28])[CH2:23][C@@:22]([CH2:40][F:41])([C:30]2[CH:35]=[C:34]([N+:36]([O-])=O)[CH:33]=[CH:32][C:31]=2F)[N:21]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])([CH3:8])([CH3:7])[CH3:6]>>[NH2:36][C:34]1[CH:33]=[CH:32][C:31]2[O:3][C@@H:2]([CH3:1])[CH2:4][C@H:23]3[S:24](=[O:29])(=[O:28])[C:25]([CH3:27])([CH3:26])[C:20]([N:12]([C:10]([O:9][C:5]([CH3:7])([CH3:6])[CH3:8])=[O:11])[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[N:21][C@:22]3([CH2:40][F:41])[C:30]=2[CH:35]=1
Reactant: C[C@H]1CO1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](CF)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Product: C[C@H]1C[C@@H]2[C@](CF)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(N)ccc2O1
Yield: 36.5 %

Procedure:
In an analogous sequence of reactions to that described in the preparation of trans intermediate 31, but using (S)-2-methyloxirane instead of 2,2-dimethyloxirane, tert-butyl N-tert-butoxycarbonyl-N-[(3S)-3-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-6,6-dimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (preparation described in the synthesis of intermediate 22) was converted to the title compound (420 mg, 0.756 mmol, 36.5%) as a white foam. MS m/z=578.0 (M+Na).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=[CH:7][N:6]2[C:18]=1[CH3:19].[CH3:20][OH:21]>>[CH3:20][O:21][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=[CH:7][N:6]2[C:18]=1[CH3:19]
Reactant: CO
Reactant: Cc1c(CCl)nc2c(NC(=O)C(C)(C)C)cccn12
Product: COCc1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Yield: 99 %

Procedure:
A solution of 12.8 g 2-chloromethyl-3-methyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 600 ml of dry methanol is refluxed for 5 h. The reaction mixture is concentrated in vacuo to half the volume. After addition of 200 ml of saturated sodium bicarbonate solution, the mixture is extracted with diethyl ether. The organic phase is washed with water and dried over anhydrous sodium sulfate. Removal of the. solvent in vacuo yields 12.5 g (99%) of the title compound (m.p. 104° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][CH3:10])[N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[NH2:15]>Cl>[CH2:9]([C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([S:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:12]([F:11])[CH:13]=2)[CH:5]=1)[CH3:10]
Reactant: Nc1ccc(Sc2ccncc2)c(F)c1
Reactant: CCc1cc(Cl)nc(N)n1
Agent: Cl
Product: CCc1cc(Nc2ccc(Sc3ccncc3)c(F)c2)nc(N)n1
Temperature: 25 °C
Yield: 3.4 %

Procedure:
2-Amino-4-chloro-6-ethylpyrimidine (Intermediate A8, 55.1 mg, 0.25 mmol) and Intermediate B7(39.4 mg, 0.25 mmol) were suspended in 0.01 M aqueous HCl (500 μL). The mixture was refluxed for 6 h. The reaction was cooled to room temperature and the solvent was evaporated by vacuum. The residue was purified by reversed phase chromatography on a YMC Pack-pro C18 column (trademark) eluting with acetonitrile/H2O (10:90-90:10 gradient). The compound was further purified by preparative TLC eluting with CH2Cl2-MeOH (90:10). Desired compound (2.9 mg, 0.0085 mmol; 34% yield); 1H NMR (Methanol-d4) 8.16 (dd, J=1.7, 4.7, 2H), 8.00-8.04 (m, 1H), 7.37 (m, 2H), 6.93 (dd, J=1.8, 4.9, 2H), 5.91 (s, 1H), 2.39 (q, J=7.7, 2H), 1.13 (t, J=7.5, 3H); ES MS [M+H]+=342; TLC (CH2Cl2-MeOH, 90:10); Rf=0.48.
Reaction SMILES: COC1C=C(C2C=CC(N3[N+](C4C=CC([N+]([O-])=O)=CC=4)=NC(C4C=CC=CC=4)=N3)=C(OC)C=2)C=CC=1N1[N+](C2C=CC([N+]([O-])=O)=CC=2)=NC(C2C=CC=CC=2)=N1.P([O-])([O-])(OC1C2C(=CC=C(Br)C=2Cl)NC=1)=O.P([O-])([O-])([O:75][C:76]1[CH:81]=[CH:80][C:79]([N+:82]([O-:84])=[O:83])=[CH:78][CH:77]=1)=O>>[CH:78]1[C:79]([N+:82]([O-:84])=[O:83])=[CH:80][CH:81]=[C:76]([OH:75])[CH:77]=1
Reactant: O=[N+]([O-])c1ccc(OP(=O)([O-])[O-])cc1
Agent: COc1cc(-c2ccc(-n3nc(-c4ccccc4)n[n+]3-c3ccc([N+](=O)[O-])cc3)c(OC)c2)ccc1-n1nc(-c2ccccc2)n[n+]1-c1ccc([N+](=O)[O-])cc1
Agent: O=P([O-])([O-])Oc1c[nH]c2ccc(Br)c(Cl)c12
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
To develop color in the two detection systems, coverslips with bound conjugates were rinsed briefly in alkaline buffer (Tris-HCl 100 mM; 100 mM NaLl, 50 mM MgCl2, pH 9.5) and the phosphatase reaction was developed in this buffer containing 40 mM of nitroblue tetrazolium and 40 mM 5-bromo-4-chloro-3 indolyl phosphate (alternatively, it may be possible to utilize the chromogenic phosphatase substrate p-nitrophenyl phosphate which can be enzymatically cleaved by alkaline phosphatase to yield soluble colored p-nitrophenol). Slides were monitored microscopically for the deposition of a purple reaction product at incorporation sites and the reaction was stopped prior to overdevelopment (5-60 minutes) by immersion in stop buffer (10 mM Tris-HCl, 5 mM EDTA; pH 8.0). Coverslips were air dried and mounted onto slides with Permount for evaluation and photomicroscopy.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Br.[NH2:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][C:11]([Br:16])=[CH:10][N:9]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:7][C:8]1[C:13]([CH2:14][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:12][C:11]([Br:16])=[CH:10][N:9]=1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: COCCN
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNCc1cc(Br)cnc1N
Reaction time: 8 h
Yield: 89.6 %

Procedure:
2-Methoxyethylamine (1.49 mL, 17.16 mmole) was added to a solution of 2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (1.49 g, 4.29 mmole) and DIEA (2.24 mL, 12.87 mmole) in CH2Cl2 (10 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the solution was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to afford the title compound (1.00 g, 90%) as a light brown liquid after drying in vacuo: MS (ES) m/e 260/262 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:14][N:10]([CH2:11][CH2:12][CH2:13]1)[CH2:9][CH2:8][CH2:7]2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O.[OH-].[Na+]>O1CCCC1>[N:10]12[CH2:14][C:6]([CH2:4][OH:3])([CH2:13][CH2:12][CH2:11]1)[CH2:7][CH2:8][CH2:9]2
Reactant: CCOC(=O)C12CCCN(CCC1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC12CCCN(CCC1)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
A solution of 1-azabicyclo[3.3.1]nonane-5-carboxylic acid ethyl ester (9.08 g, 46 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise to a cooled (-10° C.) solution of 1.0N lithium aluminum hydride/tetrahydrofuran (50 mL, 50 mmol) in a 3-neck, 250-mL flask under nitrogen at a rate to keep the reaction temperature below, 5° C. The mixture was stirred for 15 minutes at room temperature, refluxed for 45 minutes, cooled (0° C.), and carefully treated dropwise with water (2 mL), 15% sodium hydroxide (2 mL), and water (6 mL). The suspension was filtered through Celite and the solid was washed with tetrahydrofuran. The filtrate was concentrated in vacuo to afford 6.99 g (98%) of colorless solid; mp 64.0°-65.5° C.
Reaction SMILES: [CH:1]1([CH2:6]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH:12]=[N:11][C:10]([SH:13])=[N:9]1.C[O-].[Na+]>CO>[NH:8]1[CH:12]=[N:11][C:10]([S:13][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:9]1
Reactant: Sc1nc[nH]n1
Reactant: BrCC1CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(SCC2CCCC2)n[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.3 %

Procedure:
Cyclopentylmethyl bromide (21 g; 0.13 mol) was added in one portion to 1,2,4-triazole-3-thiol (12.3 g; 0.12 mol) and sodium methoxide (7.1 g; 0.13 mol) in dry methanol (100 ml) under dry nitrogen. The mixture was stirred at room temperature for 3 days, refluxed for 3 h and evaporated. The residue was dissolved in ethyl acetate (200 ml) and water (100 ml), the organic phase separated, washed with water (100 ml), dried (Na2SO4), filtered and evaporated, to afford cyclopentylmethyl 1,2,4-triazol-3-yl sulfide (18.1 g; 82%) as a waxy, off-shite solid, m.p. 48°-55° C.
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]1=[O:24])(=O)=O.O[C:26]1[CH:27]=[CH:28][C:29]([C:32]([O:34][CH3:35])=[O:33])=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:8]2[CH2:9][CH2:10][C@H:6]([O:5][C:26]3[CH:27]=[CH:28][C:29]([C:32]([O:34][CH3:35])=[O:33])=[N:30][CH:31]=3)[C:7]2=[O:24])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
(R)-tert-Butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 0.20 g, 0.55 mmol) was added to a mixture of methyl 5-hydroxypicolinate (0.10 g, 0.66 mmol), and potassium carbonate (0.099 g, 0.72 mmol) in DMF (1.6 mL). The mixture was stirred at 60° C. overnight and then cooled to ambient temperature. The mixture was partitioned between saturated aqueous NH4Cl (40 mL) and EtOAc (100 mL). The organic phase was washed successively with water (40 mL), water (40 mL) and brine (40 mL). The combined organic phases were dried over MgSO4, filtered and concentrated. The residue was purified on silica (eluting with EtOAc) to afford (S)-methyl 5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)picolinate (0.19 g, 0.45 mmol, 81%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:20]C1C=C2C(C=CN2)=CC=1>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Product: Fc1ccc2c(C3=CCC4(CC3)OCCO4)c[nH]c2c1
Yield: 96.3 %

Procedure:
This compound was prepared in the manner described for intermediate 1a by replacing indole with 6-fluoroindole (5.14 g, 38 mmol) ) to afford 10 g (96.3%) of the title compound as a white solid: mp 196-197° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](B(O)O)[CH:36]=2)[CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:35]3[CH:36]=[C:37]4[C:32]([CH:31]=[CH:30][N:29]=[CH:28]4)=[CH:33][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1ccc2ccncc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc3ccncc3c2)c1

Procedure:
A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 60 mg, 0.134 mmol), isoquinolin-7-ylboronic acid (35 mg, 0.202 mmol), 2 M Na2CO3 (0.134 mL) and DME (4 mL) was flushed with argon. PdCl2(dppf)(CH2Cl2) (11 mg, 0.013 mmol) was added and the mixture was subjected to MW irradiation at 140° C. for 30 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound as a beige powder. LC-MS (Condition 6) tR=1.33 min, m/z=495.1 [M+H]+.