Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1>C(#N)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:10]2[CH2:11][CH2:12][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8][CH2:9]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cn(C2CCNCC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Nc1c(F)c(N2CCC(n3ccnn3)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 44.4 %

Procedure:
4-(1,2,3-triazol-1-yl)piperidine hydrochloride (126 mg, 0.66 mmol) and DBU (130 mg, 0.85 mmol) were added to a suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.34 mmol) in acetonitrile (10 ml). The reaction mixture was refluxed for 24 hrs and then concentrated to dryness. The residue was diluted with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 65 mg of the desired product. m.p. 274°-276° C.; 1H NMR (TFA) δ: 9.38 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 5.25 (m, 1H), 4.60 (m, 1H), 4.15 (m, 2H), 3.80 (m, 2H), 2.65 (m, 4H), 1.34-1.70 (m, 4H).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][C:4]1([OH:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.[CH3:21][NH:22][CH3:23]>CCO>[CH3:21][N:22]([CH3:23])[CH2:20][CH:2]([OH:1])[CH2:3][C:4]1([OH:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2
Reactant: OC1(CC2CO2)c2ccccc2CCc2ccccc21
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)CC1(O)c2ccccc2CCc2ccccc21
Yield: 36.7 %

Procedure:
A mixture of 3.7 g (14 mmol) of the epoxide 11, 26.8 g (0.59 mol) of anhydrous dimethylamine, and 50 ml of EtOH was heated at 100° C. in a stainless steel autoclave for 12 hrs. When cool the contents were removed and concentrated under reduced pressure. Recrystallization of the solid residue from aqueous EtOH afforded 1.6 g (37% yield) of the crystalline amino-diol 12, m.p. 144°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].[CH3:27][O:28][CH2:29][CH:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:32][CH:30]([CH3:31])[CH2:29][O:28][CH3:27])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: COCC(C)N
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Product: COCC(C)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Yield: 68.6 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.48 g, 1.16 mmol), prepared substantially as described in Part C of Example 19a, and 2-methoxy-1-methyl-ethylamine (0.21 g, 2.32 mmol) were treated substantially as described in Part C of Example 19a to produce 0.28 g (68%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 351.8 [(M+H)+, 90].
Reaction SMILES: C1C(=O)OC(=O)C=1.[Na+].[Cl-:9].[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].[OH-:15].[Na+]>O>[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].[Cl:9][C:10]([Cl:11])([OH:15])[CH2:12][CH3:13]
Reactant: [Cl-]
Reactant: [OH-]
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: ClCC1CO1
Solvent: O
Product: CCC(O)(Cl)Cl

Procedure:
A sulfonation flask is charged with 87.5 pans of hydrolysed polymaleic anhydride (0.5 COOH equivalents, molecular weight 500-2,000, e.g. Belclene® 200), 80 parts of water and 3 parts of NaCl. After 31 parts of epichlorohydrin have been added, the reaction mixture is heated to 80°-85° C. for about 1 hour, cooled down to room temperature and neutralised with sodium hydroxide solution (pH about 6.8). Excess epichlorohydrin and dichloropropanol formed in the course of the reaction are then distilled off azeotropically. After adjustment to a solids concentration of 50%, the product is a mixture of 35% of polymer, 15% of 3-chloro-1,2-propanediol and 50% of water.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[C:15](=[C:16]([NH:25][CH:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH2:28][CH2:27]4)[N:17]=[CH:18][N:19]=3)[C:14]1=2)[C:10]#[N:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:38][Li].O.OO>CO>[Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[C:15](=[C:16]([NH:25][CH:26]4[CH2:27][CH2:28][CH:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:30][CH2:31]4)[N:17]=[CH:18][N:19]=3)[C:14]1=2)[C:10]([NH2:11])=[O:38])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: [Li]O
Reactant: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Agent: OO
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC(C[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanenitrile (180 mg, 0.33 mmol, 1.00 equiv) in methanol (5 mL) was added LiOH.H2O (40 mg, 0.95 mmol, 3.00 equiv) and 0.5 mL of H2O2 (30%) at 0° C. The resulting solution was stirred for 1 h at 0° C. and then quenched with saturated aqueous Na2SO3, diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 130 mg (70%) of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanamide as a white solid. MS: m/z 560 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][S:12]([C:15]1([CH2:18]O)[CH2:17][CH2:16]1)(=[O:14])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][C:15]2([S:12]([CH3:11])(=[O:14])=[O:13])[CH2:17][CH2:16]2)=[CH:4][C:3]=1[CH3:10]
Reactant: CS(=O)(=O)C1(CO)CC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2(S(C)(=O)=O)CC2)cc(C)c1Br
Temperature: 0 °C
Reaction time: 48 h

Procedure:
4-bromo-3,5-dimethylphenol, (306 mg, 1.52 mmol), (1-Methanesulfonyl-cyclopropyl)-methanol (228 mg, 1.52 mmol), and triphenylphosphine (399 mg, 1.52 mmol) are suspended in dry tetrahydrofuran (10 mL) and cooled to 0° C. Di-tert-butylazodicarboxylate (350 mg, 1.52 mmol) is added and the mixture stirred at 50° C. for 48 hours then at room temperature for a further 48 hours. The mixture is concentrated under vacuum then partitioned between water and dichloromethane, The organic phase is dried and the solvent removed under vacuum. The residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane) to give the title compound as a crude material which was used without further purification (Yield 664 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28](C)[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33][C@H]1CC[C@H](N)CC1>>[CH3:32][O:33][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:11]([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: CO[C@H]1CC[C@H](N)CC1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Product: CO[C@H]1CC[C@H](N(CCCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using trans-4-methoxy-cyclohexylamine,
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:14]=[C:13]([C:15]([OH:17])=O)[NH:12][N:11]=1)([O-:9])=[O:8].[CH:18]1([NH2:21])[CH2:20][CH2:19]1.N1C=CC=CC=1>ClCCl.C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH:18]1([NH:21][C:15]([C:13]2[NH:12][N:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:14]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
Oxalyl chloride (8.75 mL, 100 mmol) was added to a suspension of 3-nitro-1H-pyrazole-5-carboxylic acid (7.85 g, 50 mmol) in dichloromethane (100 mL) and THF (5.00 mL) at 0° C. and one drop of DMF was then added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was redissolved in dichloromethane (100 mL). To the reaction mixture was added a solution of cyclopropanamine (4.16 mL, 60.0 mmol) and pyridine (8.09 mL, 100 mmol) in dichloromethane (10 mL) over a period of 10 minutes. The reaction mixture was stirred overnight and then diluted with ethyl acetate (50 mL), washed with water, dried over MgSO4 and concentrated in vacuo. The crude was purified by silica gel column chromatography (0-5% 2N NH3/CD3ODichloromethane) to give 9.16 g of N-cyclopropyl-3-nitro-1H-pyrazole-5-carboxamide. MS (ESI) m/z 197.1 (M+H). 1H NMR (CD3OD) δ ppm 7.38 (s, 1H), 2.81-2.86 (m, 1H), 0.82 (td, J=7.08, 5.36 Hz, 2H), 0.62-0.68 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](F)=[C:12]([CH:15]=1)[C:13]#[N:14].[CH3:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>CN(C=O)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:19]2[C:18]([CH3:17])=[CH:22][N:21]=[CH:20]2)=[C:12]([CH:15]=1)[C:13]#[N:14]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cncn1-c1ccc(Br)cc1C#N
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 2.3 %

Procedure:
Potassium carbonate (2.07 g) was added to a DMF (20 mL) solution of 5-bromo-2-fluorobenzonitrile (2.00 g) and 4-methylimidazole (1.23 g) and the reaction solution was agitated at 100° C. for 4.5 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system), and 5-bromo-2-(4-methyl-1H-imidazol-1-yl)benzonitrile (962 mg) and 5-bromo-2-(5-methyl-1H-imidazol-1-yl)benzonitrile (60 mg) were obtained.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].CO>C(Cl)Cl>[CH3:14][N:15]([CH:17]=[C:11]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]1=[O:10])[CH3:16]
Reactant: O=C1CCCc2ccccc21
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Solvent: CO
Product: CN(C)C=C1CCc2ccccc2C1=O
Temperature: 25 °C

Procedure:
The 3,4-dihydro-2-(dimethylaminomethylene)-1(2H)-naphthalenone starting material was prepared by heating a mixture of α-tetralone (5.85 g, 40 mmol) and N,N-dimethylformamide dimethyl acetal (32 ml, 240 mmol) at 110° for 3 h. The reaction was allowed to cool to room temperature and excess reagent removed in vacuo to give a thick oil. This crude material was subjected to column chromatography (silica, 5% methanol in CH2Cl2) to afford the desired product as a thick orange oil (3.50 g). δH (CDCl3) 8.02 (1 H, dd, J 7.7, 1.5 Hz), 7.72 (1 H, s), 7.36 (1 H, td, J 7.3, 1.6 Hz), 7.28 (1H, td, J 7.6, 1.5 Hz), 7.15 (1H, dm, J 7.3 Hz), 3.12 (6H, s) and 2.98-2.80 (4H, m). MS (ES+) 202 (MH+, 90%), 175 (MH+−HCN, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[N:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: Cc1ccc(CO)nc1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(COc2nc(N)nc(-c3ccccn3)c2C#N)nc1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 5-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23](Cl)[CH:24]=3)[CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:15]=2)=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncc(Cl)cc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)on1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 10.8 %

Procedure:
To a solution of 3-(5-(4-benzyloxy-benzyl)-isoxazol-3-yl)-5-chloro-pyridin-2-ylamine (50 mg, 0.13 mmol) described in Manufacturing Example 29-2-3 in N-methylpyrrolidinone (2 mL) were added formic acid (7.3 μL, 0.19 mmol), N,N-diisopropylethylamine (67 μL, 0.38 mmol) and tetrakis(triphenylphosphine)palladium (0) (15 mg, 13 μmol) under nitrogen atmosphere at room temperature, which was stirred for 2 hours and 20 minutes at 100° C. Water and ethyl acetate were added to the reaction solution at room temperature, which was then filtered through a Celite pad. The filtrate was partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) and then purified again by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (5 mg, 11%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=C(F)C=2)=[CH:8][C:7]1=[O:21]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]1=[O:21]
Reactant: O=c1cc(OCc2cccc(F)c2)ccn1Cc1cccc(F)c1
Agent: [Pd]
Solvent: CO
Product: O=c1cc(O)ccn1Cc1cccc(F)c1
Yield: 78.9 %

Procedure:
According to Scheme 13 Step 2: A suspension of 1-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)pyridin-2(1H)-one (1 eq, 0.95 mmol, 0.29 g) and Pd/C (0.3 eq, 0.29 mmol, 30.3 mg) in MeOH (3 mL) was hydrogenated until complete (30 min). The suspension was filtered through celite and the filtrate concentrated under vacuum to afford 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (0.75 mmol, 0.16 g, 79%) as a white powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[N:17]=[CH:18][C:19]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH:42]3[CH2:47][CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43]3)(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[N:20][C:21]=1[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1)=O)(C)(C)C>C(Cl)Cl>[C:27]1([C:24]2[CH:23]=[C:22]([C:21]3[C:16]([NH2:15])=[N:17][CH:18]=[C:19]([C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH:42]5[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]5)(=[O:41])=[O:40])=[CH:37][CH:38]=4)[N:20]=3)[O:26][N:25]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(-c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4cc(-c5ccccc5)no4)n3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2ccc(S(=O)(=O)C3CCCNC3)cc2)nc1-c1cc(-c2ccccc2)no1
Temperature: 25 °C

Procedure:
TFA (500 μL, 6.490 mmol) was added to a stirred solution of tert-butyl 3-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (144 mg, 0.1890 mmol) in DCM (5 mL) and the reaction stirred at ambient temperature over night. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 5 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo. The residue was tritruated from MeOH and the precipitate isolated by filtration to give 3-(3-phenylisoxazol-5-yl)-5-(4-(piperidin-3-ylsulfonyl)phenyl)pyrazin-2-amine Compound I-1 as an orange solid (39 mg, 45% Yield). H NMR (400.0 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.39 (d, 2H), 8.05-8.02 (m, 2H), 7.92 (d, 2H), 7.80 (s, 1H), 7.61-7.55 (m, 3H), 7.21 (br s, 1H), 3.32-3.30 (m, 1H), 3.24-3.20 (m, 1H), 3.12-3.08 (m, 1H), 2.82-2.79 (m, 1H), 2.29-2.26 (m, 1H), 2.01-1.97 (m, 1H), 1.67-1.63 (m, 1H), 1.54-1.45 (m, 1H) and 1.37-1.31 (m, 1H) ppm; LC/MS m/z 462.1 [M+1]+.
Reaction SMILES: P(Br)(Br)Br.Br[CH2:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[CH:10][CH:11]=1.[NH:21]1[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]1=[O:23].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C=O)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[O:8][C:7]([CH2:6][N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])=[CH:11][CH:10]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)o1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1ccn(Cc2ccc(-c3ccccc3[N+](=O)[O-])o2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.8 %

Procedure:
To a solution of alcohol in dichloromethane at 0° C. was added neat PBr3 in ice bath. The solution was allowed to warm to 25° C. and then stirred for 12 h. The reaction was quenched with ice and extracted with ethyl acetate. The combined organic layers were washed with H2O, sat. NaHCO3 and brine, and dried over anhydrous Na2SO4. After the solution was filtered and concentrated under reduced pressure, the crude compound was used for the subsequent alkylation without further purification. To a solution of 2-(bromomethyl)-5-(2-nitrophenyl)furan 11a (120 mg, 0.43 mmol) and uracil (476 mg, 4.3 mmol) in anhydrous DMF (2.0 mL) was added anhydrous potassium carbonate (235 mg, 1.7 mmol) at 25° C. The resulting solution was then heated at 50° C. for 8 h. After removal of DMF under reduced pressure, the residue was diluted with CHCl3 and washed three times with water. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate to afford 90 mg (68%) of the uracil 13a as a white solid. 1H NMR (DMSO) δ: 11.29 (1H, s), 7.82 (1H, d, J=8.1 Hz), 7.77 (1H, d, J=7.5 Hz), 7.68 (1H, t, J=7.2 Hz), 7.60 (1H, d, J=7.8 Hz), 7.52 (1H, t, J=8.1 Hz), 6.83 (1H, d, J=3.6 Hz), 6.53 (1H, d, J=3.3 Hz), 5.57 (1H, dd, J=7.8, 1.5 Hz), 4.88 (2H, s); 13C NMR (DMSO) δ: 164.08, 151.69, 151.07, 148.39, 147.33, 145.33, 132.91, 129.70, 129.04, 124.36, 122.84, 110.38, 111.18, 102.01, 43.74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:14])([CH3:13])[C:11]#[CH:12].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COC(C)(C)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)I.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][C:10]([CH3:14])([CH3:13])[CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)C#Cc1cc(Cl)ncn1
Temperature: 45 °C
Reaction time: 6 h
Yield: 47.8 %

Procedure:
Under an atmosphere of a nitrogen gas, 2.98 g of 4,6-dichloropyrimidine, 1.81 g of 3,3-dimethyl-1-butyne, 351 mg of dichlorobis(triphenylphosphine)palladium, 381 mg of copper iodide, 4.05 g of triethylamine and 525 mg of triphenylphosphine was added to 20 ml of acetonitrile and the suspension was stirred for 6 hours at 45° C. After cooling the reaction mixture was diluted with t-butyl methyl ether and washed three times with water. The organic layers were dried over sodium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 1.86 g of 4-chloro-6-(3,3-dimethyl-1-butynyl)pyrimidine.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:24]1[O:25][CH:26]=[N:27][N:28]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:20]([C:15]1[CH:14]=[C:13]([CH2:12][CH:11]([NH2:10])[C:24]2[O:25][CH:26]=[N:27][N:28]=2)[CH:18]=[CH:17][C:16]=1[OH:19])([CH3:23])([CH3:21])[CH3:22]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(CC(NC(=O)OCc2ccccc2)c2nnco2)ccc1O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(CC(N)c2nnco2)ccc1O
Yield: 96.9 %

Procedure:
To a solution of 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,3,4-oxadiazol-2-yl)ethylcarbamic acid benzyl ester (1.25 g, 3.16 mmol) in methanol (30 ml), 10% palladium carbon (130 mg) was added and stirred in a hydrogen atmosphere at room temperature for 1 day. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=100:10:1), giving the titled compound (0.80 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[CH:22]=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[Cl:34][C:35]([Cl:40])([Cl:39])[C:36](Cl)=[O:37]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:36](=[O:37])[C:35]([Cl:40])([Cl:39])[Cl:34])=[CH:23][CH:24]=[C:13]3[CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: O=C(c1ccc2n1Cc1ccccc1N(S(=O)(=O)c1ccc(Br)cc1)C2)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 21 h
Yield: 62.9 %

Procedure:
To a solution of 10-[(4-bromophenyl)sulfonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (2.32 g, 5.753 mmol) and N,N-dimethylaniline (1.17 mL, 9.204 mmol) in dry dichloromethane (20 mL) at 0° C. under nitrogen was added dropwise trichloroacetyl chloride (0.96 mL, 8.629 mmol). The ice bath was removed and the reaction mixture stirred at room temperature for 21 hours. The reaction mixture was then washed with 2 M hydrochloric acid (2×100 mL) and water (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give an olive foam. Purification by flash chromatography using a solvent gradient of 5-15% ethyl acetate in hexane afforded a cream solid that was recrystallized from diethyl ether/hexane to afford the title compound (1.986 g, 63%) as an off-white crystalline solid, m.p. 182-183 ° C.