Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[CH:3]=1.[CH2:9]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH2:10][CH2:11][C:12]#[CH:13].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)c1
Reactant: C#CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCC#Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Bromo-3-fluoro-benzene (1.0 mL, 7.8 mmol), 2-pent-4-ynyl-isoindole-1,3-dione (1.8 g, 8.6 mmol), Pd(PPh3)2Cl2 (191 mg, 0.27 mmol), CuI (118 mg, 0.62 mmol), and triethylamine (4.4 mL, 31.3 mmol) were taken up into DMF (10 mL) and stirred at room temperature for four hours. The reaction was then quenched with saturated NaHCO3 and the resulting mixture extracted with EtOAc and washed with brine, then dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified on normal phase chromatography (Heptane/EtOAc) to yield 2-(5-(3-bromophenyl)pent-4-ynyl)isoindoline-1,3-dione. MH+ 368, 370
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)c1ccnc(-c2ccccc2Cl)c1
Temperature: 110 °C
Yield: 89.1 %

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyridine (4 g, 22.0 mmol), 2-chlorophenylboronic acid (5.04 g, 24.2 mmol), Ba(OH)2 (12.5 g, 66.1 mmol) and Pd(PPh3)2Cl2 (464 mg, 0.66 mmol) in DME (140 mL)/water (35 mL) was heated at 110° C. for 1 h. The solids were filtered off and the mother liquor were concentrated to around 80 mL and extracted with EtOAc. The organic layer was washed with brine, then water, dried (MgSO4), filtered and concentrated. Purification by column chromatography (1/1 Petroleum ether/EtOAc) gave the Suzuki adduct (5.05 g, 89%) as a colourless oil.
Reaction SMILES: C([N:3](CC)CC)C.[ClH:8].Cl.[N:10]1([CH2:15][CH:16]([N:18]2[C:31]3[CH:30]=[C:29]([C:32](=[NH:36])OCC)[CH:28]=[CH:27][C:26]=3[S:25][C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[ClH:8].[N:10]1([CH2:15][CH:16]([N:18]2[C:31]3[CH:30]=[C:29]([C:32]([NH2:36])=[NH:3])[CH:28]=[CH:27][C:26]=3[S:25][C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCN(CC)CC
Reactant: CCOC(=N)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Agent: Cl
Solvent: CCO
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=N)N)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Triethylamine (8.4 cc) is added to a solution of ethyl 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboximidate dihydrochloride (13.63 g) in absolute ethanol (150 cc), and the reaction mixture is diluted with dry ethanol (100 cc). Gaseous ammonia is bubbled for 4 hours into the reaction mixture, which is then stirred for 12 hours at 25° C. The suspension obtained is filtered on sintered glass and the filtrate is concentrated to dryness at 25° C. under reduced pressure (30 mm Hg; 4 kPa) to give a yellow product of meringue-like consistency, which is purified by chromatography on a column of alumina (height: 23 cm; diameter: 4 cm), eluting with mixtures of methylene chloride and methanol in proportions of 95:5 (750 cc) and 50:50 (1,500 cc) and collecting 125-cc fractions. The first 900 cc of eluate are discarded and fractions 8 to 11 are combined and concentrated to dryness at 25° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamidine hydrochloride (4.5 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:30]([NH:33][C:34]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:14][CH:15]=2)[CH2:20]1)=[O:35])([CH3:32])[CH3:31]
Reactant: CC(C)N=C=O
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
A 10 mL CH2Cl2 solution of 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (254 mg, 0.73 mmol), NEt3 (0.20 mL, 1.4 mmol), isopropyl isocyanate (192 mg, 2.2 mmol), and 4-dimethylaminopyridine (12 mg, 0.1 mmol) is stirred under N2, at room temperature for 18 hours. The reaction mixture is concentrated and the residue is purified by chromatography (SCX-MeOH wash, elute 2M NH3/MeOH; then SiO2; 0-10% MeOH/CH2Cl2/1% NH4OH gradient) to give pure product (110 mg, 42% yld). MS(ES+) 360.2(M+H)+.
Reaction SMILES: [C:1]([NH:3][C:4]1[CH:25]=[C:24]([CH3:26])[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:23])=[C:13]([CH:22]=2)[C:14]([N:16]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH3:17])=[O:15])=[C:6]([CH3:27])[CH:5]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>>[CH:18]1([N:16]([CH3:17])[C:14](=[O:15])[C:13]2[CH:22]=[C:9]([O:8][C:7]3[C:6]([CH3:27])=[CH:5][C:4]([NH:3][C:1]4[NH:30][N:29]=[N:28][N:2]=4)=[CH:25][C:24]=3[CH3:26])[CH:10]=[CH:11][C:12]=2[OH:23])[CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(NC#N)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1cc(Nc2nnn[nH]2)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Temperature: 165 °C

Procedure:
N-Cyclobutyl-5-[2,6-dimethyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide was prepared from 5-(4-cyanoamino-2,6-dimethyl-phenoxy)-N-cyclobutyl-2-hydroxy-N-methyl-benzamide according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (1.2 equiv) and ammonium chloride (10 equiv) were used, and the reaction was heated to 165° C. for 5 hours. After the reaction had been acidified, the aqueous mixture was washed with ethyl acetate (3×10 ml). The combined organic extracts were extracted with aqueous 1N HCl (3×50 ml), and brine (50 ml). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (methanol:water:dichloromethane 15:1.5:83.5) to afford the title product of Example 6. MS (APCI+) Calc.: 408.5, Found: 409.2 (M+1).
Reaction SMILES: [O:1]1[CH2:10][CH:2]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH2:15])[CH:12]([CH3:14])[CH3:13]>O>[C:4]1([CH2:3][CH:2]([OH:1])[CH2:10][NH:15][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)CN
Reactant: c1ccc(CC2CO2)cc1
Solvent: O
Product: CC(C)CNCC(O)Cc1ccccc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
2,3-Epoxypropyl benzene (10 g, 74.5 mmol) and isobutylamine (5.4 g, 74.5 mmol) were mixed then treated with water (2 mL). The mixture was stirred overnight at 110° C., then distilled to yield N-(3-phenyl-2-hydroxypropyl)N-isobutylamine (6.5 g): bp 115-117° C. (1 mmHg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:34]3[CH2:35][C:36](=[O:38])[CH2:37][CH:30]2[CH2:31][O:32][CH2:33]3)[CH2:10]1)(=[O:8])=[O:7].C1COCC1.[BH4-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH:30]3[CH2:37][CH:36]([OH:38])[CH2:35][CH:34]2[CH2:33][O:32][CH2:31]3)[CH2:10]1)(=[O:7])=[O:8]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2CC(=O)C3)cc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2CC(O)C3)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.8 %

Procedure:
A 25-mL round-bottomed flask was charged with 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (60 mg, 0.11 mmol, Example 106), THF (3 mL) and MeOH (0.5 mL). NaBH4 (39.6 mg, 1.05 mmol) was added and the reaction stirred at room temperature for 20 min. MeOH (50 mL) was added and then the mixture was concentrated onto silica gel and purified via column chromatography (12 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 9-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (10 mg) as a mixture of two isomers.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(OC)(O[CH3:18])(=O)=O>>[CH3:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COS(=O)(=O)OC
Product: COc1ccc(-c2ccccc2)cc1

Procedure:
Methylation of 4-hydroxybiphenyl is carried out with dimethyl sulphate according to a conventional method.
Reaction SMILES: O1[C:6]2[C@H:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:3](=[O:25])[C:2]1=2.[ClH:26].C(=O)([O-])O.[Na+]>CC(C)=O>[Cl:26][C:2]1[C:3](=[O:25])[C:4](=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=1
Reactant: Cl
Reactant: CCCCCCC=C[C@@H]1C(=CCCCCCC(=O)OC)C(=O)C2=C1O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCC=C[C@H]1C=C(Cl)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 0.5 h
Yield: 65 %

Procedure:
16 mg (46 microliters) of (4R)-2,3-epoxy-4-(1-octenyl)-5-(6-methoxylcarbonylhexylidene)cyclopentenone was dissolved in 1 ml of acetone. To the solution was added 0.1 ml of concentrated hydrochloric acid, and then the mixture was stirred for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried product was concentrated and subjected to silica gel column chromatography (silica gel, 5 g; eluent, hexane:ethyl acetate=15:1→6:1) to give 11 mg (yield 65%) of (4S)-2-chloro-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone.
Reaction SMILES: [F:1][C:2]([F:32])([C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[N+:33]([C:36]1[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[CH:38][C:37]=1F)([O-:35])=[O:34].CN1C(=O)CCC1>C(N(CC)CC)C>[F:1][C:2]([F:32])([C:25]1[CH:26]=[C:27]([NH:31][C:37]2[CH:38]=[CH:39][C:40]([N+:42]([O-:44])=[O:43])=[CH:41][C:36]=2[N+:33]([O-:35])=[O:34])[CH:28]=[CH:29][CH:30]=1)[C:3]([F:23])([F:24])[C:4]([F:21])([F:22])[C:5]([F:19])([F:20])[C:6]([F:17])([F:18])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Nc2cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2)c([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
A mixture of 3-(perfluoro-n-octyl)benzenamine (2.04 g), 2,4-dinitrofluorobenzene (0.78 g), NMP (8 mL) and triethylamine (0.85 mL) was heated to 70° C. for 16 hr. Extraction and recrystallization from hexane-ethyl acetate gave N-[3-(perfluorooctyl)phenyl]-2,4-dinitrobenzenamine (2.25 g, mp 124.5-125° C.).
Reaction SMILES: [OH-].[Na+].S(OC)(O[CH3:7])(=O)=O.[C:10]1([C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:17][CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH2:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[CH3:7][NH:20][C@H:19]([C:21]([OH:23])=[O:22])[CH2:18][S:17][C:16]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COS(=O)(=O)OC
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 90 °C

Procedure:
1.5 cm3 of 33% (w/w) sodium hydroxide solution, followed by 1.5 cm3 of dimethyl sulphate, are added, with stirring, to a suspension of 3.75 g of S-triphenylmethyl-L-cysteine in 15 cm3 of water. The reaction mixture is heated with stirring at 90° C. until a clear solution is obtained and is then heated at reflux for 2 hours. After cooling, the precipitate obtained is filtered off and washed with water and then with diethyl ether. 1.95 g of N-methyl-S-triphenylmethyl-L-cysteine are thus obtained, melting at 114° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:46]=[CH:47][CH:48]=1)[C:34]([NH:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[N:41][CH:42]=1)=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:39]2[CH:38]=[C:37]([NH:36][C:34](=[O:35])[C:33]3[CH:46]=[CH:47][CH:48]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH:42]=[N:41][CH:40]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1cccc(C(=O)Nc2cncc(B(O)O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(C(=O)Nc2cncc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added (5-(3-methoxybenzamido)pyridin-3-yl)boronic acid (120 mg, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) and 148 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by flash chromatography (50 to 100%, hexane-ethyl acetate) phase using SP1® Purification System to give 113 mg (85% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [S:1]1[C:13]2[N:5]([C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[C:8]([CH2:14][OH:15])[CH:7]=3)[CH2:4][CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[S:1]1[C:13]2[N:5]([C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[C:8]([CH:14]=[O:15])[CH:7]=3)[CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccc2nc3n(c2c1)CCCS3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2nc3n(c2c1)CCCS3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottomed flask was loaded 1.1 grams of (3,4-Dihydro-2H-1-thia-4a,9-diaza-fluoren-6-yl)-methanol, 6 grams of manganese dioxide and 250 ml chloroform. The mixture was stirred for one hour at room temperature and then filtered through a pad of celite. This yielded 0.67 grams of product (61%). MS: 219.0 (M+H). H-NMR (CDCl3): δ 10.04 (s, 1H), 7.67 (m, 3H), 4.25 (m, 2H), 3.27 (m, 2H), 2.50 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C@@:6]1([NH:11][C:12](=[O:48])[C@@H:13]2[CH2:17][C@@H:16]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:20]=3)[CH2:15][N:14]2[C:37]([NH:39][NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:38])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-].Cl>C1COCC1.CO>[CH2:41]([NH:40][NH:39][C:37]([N:14]1[CH2:15][C@H:16]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=3)[N:22]=[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:20]=2)[CH2:17][C@H:13]1[C:12]([NH:11][C@:6]1([C:4]([OH:5])=[O:3])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:48])=[O:38])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NNCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NNCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.6 %

Procedure:
To a solution compound 106 (0.0101 mmol) in THF-MeOH 2:3 (3 ml) was added 1M LiOH 10 equiv. The solution was kept at 50° C. for 18 hrs. After cooling to RT the sample was neutralized with HCl and concentrated to dryness. The crude material was dissolved in DCM (2 ml) and a solution of TFA: TES 1:1 (1 ml) was added. The mixture was stirred for 3 hrs at RT and then concentrated to dryness. The crude material was dissolved in MeOH and purified by Prep LCMS which gave the title compound (0.6 mg). Purity by HPLC>95%. M+H+622.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH3:21][Si:22]([O:25][C:26](=[O:33])[CH2:27][O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])([CH3:24])[CH3:23]>C1COCC1>[CH2:13]([Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:33][CH:26]([O:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH2:27][O:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH3:14]
Reactant: C[Si](C)(C)OCC(=O)O[Si](C)(C)C
Reactant: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[Si](CC)(CC)OC(CO[Si](C)(C)C)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15.5 mL, 0.11 mol) in THF (100 mL) at −78° C. was added a 1.6 M hexanes solution of n-butyl lithium (70 mL, 0.11 mol) over 15 minutes. After stirring for an additional 15 minutes at this temperature, triethylsilylchloride (16.7 mL, 0.1 mol) was added over 10 minutes followed by the addition of trimethylsilyl-2 -(trimethylsiloxy)acetate (24.4 mL, 0.1 mol) over 30 minutes. The reaction was stirred at −78° C. for 30 minutes and warmed to ambient temperature by removing the cryogenic bath. The THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate out the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 min and the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product as a mixture of geometrical isomers (4:1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]#[N:13])[N:10]=1)=[O:4].[CH2:14]([C:16]1[CH:59]=[CH:58][C:19]2[CH:20]([C:30]3[C:31](=[O:57])[NH:32][C:33](=[O:56])[N:34]([C:36]4[CH:41]=[CH:40][N:39]=[C:38](NCC(NC5SC=C(CC(O)=O)N=5)=O)[N:37]=4)[CH:35]=3)[C:21]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:22]=3[CH:23]=[CH:24][C:18]=2[CH:17]=1)[CH3:15]>>[C:12]([CH2:11][C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:38]2[N:37]=[C:36]([N:34]3[CH:35]=[C:30]([CH:20]4[C:19]5[CH:58]=[CH:59][C:16]([CH2:14][CH3:15])=[CH:17][C:18]=5[CH:24]=[CH:23][C:22]5[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:21]4=5)[C:31](=[O:57])[NH:32][C:33]3=[O:56])[CH:41]=[CH:40][N:39]=2)[S:7][CH:8]=1)#[N:13]
Reactant: N#CCc1csc(NC(=O)CN)n1
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC#N)cs3)n2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of step (iii) (1.58 g) and the product of example 15 step (viii) (1.14 g) by the method of example 7 step (i). Yield 0.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[Br:13]Br>C(O)(=O)C.C(Cl)Cl>[Br:13][C:5]1[C:4]2[C:8](=[C:9]([CH:11]=[O:12])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: BrBr
Reactant: O=Cc1cc(Cl)cc2cn[nH]c12
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1cc(Cl)cc2c(Br)n[nH]c12
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-1H-indazole-7-carbaldehyde (1.0 g, 5.54 mmol) in acetic acid (5 mL) was added bromine (0.43 mL, 8.31 mmol) slowly over 5 min. After 1 h, the reaction mixture was diluted with methylene chloride, washed with water (2×), saturated sodium thiosulfate (2×), saturated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated to afford 1.4 g (97%) as a yellow powder. LC/MS (HPLC method 1): tR=2.49 min, 261.00(MH)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](F)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]([CH:22]1[CH:31]([OH:32])[C:30]2[C:25](=[CH:26][C:27]([C:33](=[N:35]O)[NH2:34])=[CH:28][CH:29]=2)[O:24][CH2:23]1)=[N+:20]=[N-:21].CCN(C(C)C)C(C)C>C(#N)C>[N:19]([CH:22]1[CH:31]([OH:32])[C:30]2[C:25](=[CH:26][C:27]([C:33]3[N:35]=[C:16]([C:10]4[O:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:11]=4[C:12]([F:15])([F:14])[F:13])[O:17][N:34]=3)=[CH:28][CH:29]=2)[O:24][CH2:23]1)=[N+:20]=[N-:21]
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: [N-]=[N+]=NC1COc2cc(C(N)=NO)ccc2C1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: [N-]=[N+]=NC1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2C1O
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride Int-1-G (273 mg, 1.05 mmol) in ACN (6.7 mL) was added racemic (3R*,4S*,E/Z)-3-azido-N′,4-dihydroxychroman-7-carboximidamide (250 mg, 1.0 mmol) and Hunig's Base (210 μL, 1.2 mmol). The resulting solution was stirred overnight. Next, the solvent was evaporated. The resulting residue was purified by column chromatography (ISCO Combiflash Companion, 12 g silica gel, 10% ethyl acetate-hexane for 5 min then ramp to 50% ethyl acetate-hexane over 7 min then 50% ethyl acetate-hexane for 3 more min, product came out 8-10 min) to give racemic (3R*,4S*)-3-azido-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-4-ol (280 mg, 0.59 mmol, 59.3% yield): LCMS=470.98 [M+H]+, 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (1H, dd, J=8.03, 1.65 Hz), 7.66-7.72 (3H, m), 7.52-7.62 (4H, m), 4.96-5.02 (1H, m), 4.43-4.51 (1H, m), 4.32-4.38 (1H, m), 4.08-4.17 (1H, m).