Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][CH2:9][CH2:10][C:3]=12.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[I:1][C:2]1[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][N:5]=[C:4]2[O:8][CH2:9][CH2:10][C:3]=12
Reactant: O=[N+]([O-])O
Reactant: Ic1ccnc2c1CCO2
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc2c(c1I)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
4-Iodo-2,3-dihydrofuro[2,3-b]pyridine (2.237 g, 9.055 mmol) in sulfuric acid (10.0 mL, 188 mmol) at −10° C. was added slowly to a stirred solution of a solution of fuming nitric acid (15.0 mL, 358 mmol) in sulfuric acid (15.0 mL, 281 mmol) slowly over a period of 15 min. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then quenched by addition onto crushed ice and the resulting mixture was extracted with EtOAc (6×100 mL). The combined organic extract was washed with saturated aq. NaHCO3 (2×300 mL) and brine (300 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a pale yellow solid (2.43 g, 92%). LCMS calc. for C7H6IN2O3(M+H)+: m/z=292.9. found 293.0.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:13]23[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH2:17][CH2:18]2)[CH2:15][O:14]3)[CH:10]=[CH:11][CH:12]=1)(=O)=O.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:34]1([S:40][C:7]2[CH:8]=[C:9]([C:13]34[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])([CH2:17][CH2:18]3)[CH2:15][O:14]4)[CH:10]=[CH:11][CH:12]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(OS(=O)(=O)C(F)(F)F)c3)(CC1)OC2
Reactant: Sc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Sc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of tert-butyl 2-(2-(1-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (80 mg, 0.162 mmol), thiophenol (0.025 mL, 0.243 mmol), XantPhos (18.72 mg, 0.032 mmol), and Pd2(dba)3 (14.8 mg, 0.016 mmol) in 1,4-dioxane (1 mL) was degassed with low vacuum under Ar five times using a sonicator. DIPEA (0.085 mL, 0.485 mmol) pre-degassed in the same way was added under an atmosphere of Ar. The mixture was heated to reflux for 2 h, then was cooled to rt, filtered, and the filtrate was concentrated in vacuo. The crude oil was chromatographed (SiO2) using a gradient from 0% to 50% EtOAc/hexane (10 min) to give the title compound (70 mg, 0.154 mmol, 95% yield) as a clear oil. LCMS: [M+Na]+=477.1. 1H NMR (CDCl3) δ: 7.48 (t, J=1.8 Hz, 1H), 7.35-7.27 (m, 6H), 7.26-7.18 (m, 2H), 3.96 (s, 2H), 3.88 (s, 2H), 3.58 (t, J=6.9 Hz, 2H), 2.06-1.97 (m, 4H), 1.73 (dd, J=9.1, 6.8 Hz, 4H), 1.51 (s, 11H).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH2:19]=O.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][CH:23]=1>CC(O)=O.O1CCOCC1.O>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([CH2:19][N:15]3[CH2:16][CH2:17][CH:12]([C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:18])[CH3:1])[CH:11]=[CH:10][CH:9]=4)[CH2:13][CH2:14]3)=[CH:27][NH:28]2)=[CH:24][CH:23]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: C=O
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]c4cc(Cl)ccc34)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.3 %

Procedure:
A solution of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.369 g, 1.50 mmol) and 37 wt % aqueous formaldehyde (30.0 mg, 1.50 mmol) in 1.00 mL of HOAc:dioxane (1:4) was added to 6-chloro-1-H-indole (0.152 g, 1.00 mmol) and the reaction mixture was stirred for 12 h at room temperature. The resulting mixture was diluted with H2O (10 mL). The aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative TLC plates using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product (79.0 mg, 42.0%): 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.04 (s, 1H), 7.52 (t, 2H, J=8.1 Hz), 7.35 (d, 2H, J=13.3 Hz), 7.18 (t, 1H, J=7.9 Hz), 7.09 (dd, 1H, J=1.9, 8.5 Hz), 6.85 (d, 1H, J=7.4 Hz), 5.18 (s, 1H), 4.01 (s, 2H), 2.55 (septet, 1H, J=6.8 Hz), 2.48-2.34 (m, 3H), 2.08-1.95 (m, 4H), 1.78 (d, 2H, J=12.8 Hz), 1.22 (d, 6H, J=6.8 Hz); ESMS m/e: 410.1 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1C=CC(C=O)=CC=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([N:40]=[CH:1][C:2]5[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[CH:4][CH:3]=5)[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Reactant: O=Cc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Product: COc1ccc(C=NC2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3)C2)cc1

Procedure:
In the described fashion of Example 1 replacing benzaldehyde with 4-hydroxybenzaldehyde and using the acid (1) (R=cyclopropyl) described in Example 19 one obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-(4-hydroxybenzylidene)amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid (3) (R=cyclopropyl, Z=p-hydroxyphenyl); m.p. 273°-275° C.; Mass Spectrum, M/Z 435. Analytical Calculation for C24H22FN3O4.1/2H2O: C, 66.21; H, 5.06; N, 9.65. Found: C, 64.83; H, 5.01; N, 9.13.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30]>CC(C)=O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=2)=[CH:3][C:2]=1[O:1][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30]
Reactant: CCOC(=O)c1csc(Nc2ccc(C)c(O)c2)n1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(Nc2ccc(C)c(OCC=C(C)C)c2)n1
Yield: 57 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of ethyl 2-(3-hydroxy-4-methylphenylamino)thiazole-4-carboxylate (80 mg, 0.29 mmol) and K2CO3 (44 mg, 0.32 mmol) in acetone (2.9 mL) was treated with 4-bromo-2-methyl-2-butene (0.037 mL, 0.32 mmol). The reaction mixture was heated at reflux for 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 57% yield (56 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25](B(O)O)=[C:24]([F:33])[CH:23]=1.[CH3:34][PH:35](=[O:37])[CH3:36]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:26]=[C:27]([O:28][CH3:29])[C:22]([P:35]([CH3:36])([CH3:34])=[O:37])=[CH:23][C:24]=2[F:33])[CH:3]=1)[CH3:11]
Reactant: C[PH](C)=O
Reactant: COc1cc(B(O)O)c(F)cc1Br
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: COc1cc(-c2cnc(N)c(OC(C)c3c(Cl)ccc(F)c3Cl)c2)c(F)cc1P(C)(C)=O

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromo-2-fluoro-5-methoxyphenylboronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3. ESMS: m/z 501 (M+H)+.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[C:13]2[N:12]([CH3:14])[CH:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C([N:23](CC1C=CC=CC=1)[CH2:24][C:25]([NH2:28])([CH3:27])[CH3:26])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH2:23][CH2:24][C:25]([NH:28][CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:13]2[N:12]([CH3:14])[CH:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:27])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)(N)CN(Cc1ccccc1)Cc1ccccc1
Reactant: Cn1cnc2cccc(OCC3CO3)c21
Agent: [Pd]
Solvent: CCO
Product: Cn1cnc2cccc(OCC(O)CNC(C)(C)CN)c21

Procedure:
10.2 g. 2,3-Epoxy-1-(3-methylbenzimidazol-4-yloxy)-propane are added to 40.3 g. 2-dibenzylamino-1,1-dimethylethylamine (prepared analogously to H. G. Johnson, J.A.C.S., 68, 12/1946) in 300 ml. ethanol and the reaction mixture is stirred for 3 days at ambient temperature. The reaction mixture is now hydrogenated at 60° C. over 8 g. palladium-charcoal (10%) until the take up of hydrogen is finished. The catalyst is then filtered off with suction and the filtrate evaporated to dryness. The residue is chromatographed on silica gel with methanol/concentrated aqueous ammonia solution (95:5 v/v). The appropriate fractions are evaporated, the residue is taken up in methylene chloride and dried over anhydrous sodium sulphate and the solution is evaporated to dryness. There are obtained 8.7 g. (66% of theory) of the desired product as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:4]2[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].C(N(CC)C(C)C)(C)C>C(O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH:20][C:2]1[CH:3]=[CH:4][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:6]2[N:7]=1
Reactant: NCc1cccc(F)c1
Reactant: COC(=O)c1cnn2cnc(Cl)cc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnn2ccc(NCc3cccc(F)c3)nc12
Yield: 80 %

Procedure:
A solution of methyl 5-chloropyrazolo[1,5-c]pyrimidine-3-carboxylate (240 mg, 1.1 mM, 1.0 equiv), 3-fluorobenzylamine (200 uL, 2.0 mM, 2.0 equiv), 30 mL of ethanol and 400 uL of N,N-diisopropylethylamine (2.0 mM, 2 equiv) were combined and heated under reflux for 4 hours. The mixture was concentrated and the product collected by filtration and washed with cold ethanol to give 271 mg (80%) of methyl 5-(3-fluorobenzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate LCMS (ESI) m+H=301.2, 1H NMR (400 MHz, DMSO-d6) δ: 8.56 (d, 1H), 8.41 (m 1H), 8.17 (s, 1H), 7.35 (m, 3H), 7.08 (td, 1H), 6.44 (d, 1H), 4.61 (d, 2H), 3.74 (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][CH2:8][C:9]1[N:13](CC2C=CC(OC)=CC=2)[C:12]([SH:23])=[N:11][N:10]=1)=[O:5])C.C(OC(COCC(NN)=O)=O)C.[OH-].[Na+]>>[C:4]([CH2:6][O:7][CH2:8][C:9]1[N:13]=[C:12]([SH:23])[NH:11][N:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)COCc1nnc(S)n1Cc1ccc(OC)cc1
Agent: CCOC(=O)COCC(=O)NN
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COCc1n[nH]c(S)n1

Procedure:
By employing a procedure similar to that described in Example XVI, Part A, 3-(ethoxycarbonylmethoxymethyl)-4-(p-methoxybenzyl)-1,2,4-triazole-5-thiol was prepared from ethoxycarbonylmethoxyacetohydrazide. The ethoxycarbonyl group was then hydrolyzed to the free acid using aqueous 2N sodium hydroxide, and the p-methoxybenzyl blocking group was thereafter removed by using trifluoroacetic acid in a manner similar to that earlier described in Example XVI, Part B to finally give pure 3-(carboxymethoxymethyl)-1,2,4-triazole-5-thiol, m.p. 180°-182° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[C:25](=O)[CH2:24][CH2:23][CH2:22]2.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl.C(O)(=O)C.O>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH2:24][CH2:23][CH2:22]2
Reactant: Cc1ccccc1N
Reactant: O=C1CCCc2cccc(Br)c21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1NC1CCCc2cccc(Br)c21
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 57.1 g (533 mmol) of 2-methylaniline in 300 ml of toluene 25.3 g (133 mmol) of TiCl4 was added dropwise for 30 min at room temperature in argon atmosphere. The resulting mixture was stirred for 30 min at 90° C. followed by an addition of 30.0 g (133.0 mmol) 8-bromo-3,4-dihydronaphthalen-1(2H)-one. This mixture was stirred for 10 min at 90° C., poured into 500 ml of water, and the product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The residue was re-crystallized from 50 ml of ethyl acetate. The obtained solid was dissolved in 600 ml of methanol, 15.4 g (244 mmol) of NaBH3CN and 5 ml of acetic acid were added in argon atmosphere. The resulting mixture was refluxed for 3 h, then cooled to room temperature, and evaporated to dryness. The residue was diluted with 500 ml of water, and crude product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The residue was re-crystallized from 400 ml of methanol. Yield 33.2 g (79%) of a yellow crystalline powder. Anal. Calc. for C17H18BrN: C, 64.57; H, 5.74; N, 4.43. Found: C, 64.69; H, 5.82; N, 4.55. 1H NMR (CDCl3): δ 7.45 (m, 1H, 7-H in tetrahydronaphtalene); 7.19 (m, 1H, 6-H in tetrahydronaphtalene); 7.08-7.14 (m, 3H, 5-H in tetrahydronaphtalene and 3,5-H in 2-methylphenyl); 6.86 (m, 1H, 6-H in 2-methylphenyl); 6.68 (m, 1H, 4-H in 2-methylphenyl); 4.78 (m, 1H, 4-H in 2-methylphenyl); 3.51 (br.s, 1H, NH); 2.86-2.92 (m, 1H, 4- or 4′-H in tetrahydronaphtalene); 2.72-2.81 (m, 1H, 4′- or 4-H in tetrahydronaphtalene); 2.30-2.34 (m, 1H, 3- or 3′-H in tetrahydronaphtalene); 2.06 (s, 3H, CH3 in 2-methylphenyl); 1.85-1.97 (m, 1H, 3′- or 3-H in tetrahydronaphtalene); 1.77-1.81 (m, 1H, 2- or 2′-H in tetrahydronaphtalene); 1.59-1.67 (m, 1H, 2′- or 2-H in tetrahydronaphtalene).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[F:22][C:23]1[CH:24]=[C:25]([CH2:30]C#N)[CH:26]=[CH:27][C:28]=1[F:29]>>[F:22][C:23]1[CH:24]=[C:25]([C:30]2[O:3][N:1]=[C:4]3[CH:5]=[CH:6][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:8][C:9]=23)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: N#CCc1ccc(F)c(F)c1
Product: Cc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(F)c(F)c4)c3c2)cc1

Procedure:
The title compound, light yellow solid (22 mg, 16%), MS (ISP) m/z=388.3 [(M+H)+], mp 198° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(3,4-difluoro-phenyl)-acetonitrile (see also example 39).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:19]=1C.[OH-].[Na+].[CH2:30](O)C>>[CH3:5][C:4]([CH3:7])([O:3][C:1]([NH:8][C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:18]1[CH:19]=[C:20]([CH3:30])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:14]([OH:16])=[O:15])=[O:2])[CH3:6]
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N[C@H](CCCN)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc([N+](=O)[O-])c(NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Yield: 61 %

Procedure:
To 696 mg (3.0 mmol) of Boc-D-Ornithine (as a 1M solution in ethanol) was added 551.5 mg (3.30 mmol) of 2-fluoro-3-nitrotoluene and 3 ml (3 mmol) of 1N sodium hydroxide. The reaction was heated to reflux for 24 hours. The reaction was concentrated/n vacuo. The product was purified by flash chromatography with acetonitrile/acetic acid/water 6/1/1. The product (620 mg, 61% yield) was obtained was a yellow oil. mp>258° C. (dec.). MS (FAB) M/Z: 268 (M+H). 1H NMR (300 MHz, CDCl3) δ: 1.7-2.0 (m, 4H), 2.1 (s, 9H), 2.45 (s, 3H), 3.40 (t, 2H), 4.00 (t, 1H), 6.60 (td, 1H), 7.10 (dd, 1H), 8.00 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[CH:5]=[C:4](Cl)[N:3]=1.O.[NH2:22][NH2:23]>O1CCOCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[CH:5]=[C:4]([NH:22][NH2:23])[N:3]=1
Reactant: Fc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1C(F)(F)F
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(Nc2ccc(F)c(C(F)(F)F)c2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a stirred solution of (2,6-dichloropyrimidin-4-yl)-(4-fluoro-3-trifluoromethylphenyl)amine (XXII) (2.5 g, 7.66 mmol) in dioxane (15 mL) was added hydrazine monohydrate (1 mL) and the mixture stirred at ambient temperature for 24 h. The mixture was diluted with water and the resulting slurry was stirred for 10 min then filtered under vacuum. The white precipitate was rinsed with water and dried under vacuum to give (2-chloro-6-hydrazinopyrimidin-4-yl)-(4-fluoro-3-trifluoromethylphenyl)amine (XXIV) as a white solid (2.1 g, 85% yield): m.p. 102-103° C., 1H NMR (CDCl3) δ 7.7 (m. 1H), 7.59 (m, 1H), 7.21 (m, 1H), 5.95 (s, 1H), 3.77 (s, 3H); ESI/MS 325 (M−H).
Reaction SMILES: C(Br)C1C=CC=CC=1.I[CH2:10][CH2:11][CH2:12][CH3:13].[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:10]([N:27]1[CH2:28][CH2:29][N:25]([C:17]2[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH3:14])[N:16]=2)[C:26]1=[O:30])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCI
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCc1ccccc1
Product: CCCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Yield: 73 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 1-iodobutane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 73% yield: NMR (300 MHZ, CDCl3) δ 4.08 (q, J=7.2 Hz, 2H), 3.99-3.85 (m, 2H), 3.47-3.33 (m, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.38 (s, 3H), 1.41-1.22 (m, 7H), 0.74 (t, J=7.2 Hz, 3H); MS (ES+) m/z 312.3 (M+1).
Reaction SMILES: [C:1]1([NH:11][C:12]2[C:13]3[CH:20]=[C:19]([C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=4)[NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:27]([N:31]=[C:32]=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:27]([NH:31][C:32]([N:24]1[CH2:23][CH:22]=[C:21]([C:19]2[NH:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[C:13]=3[CH:20]=2)[CH2:26][CH2:25]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N=C=O
Reactant: C1=C(c2cc3c(Nc4cccc5ccccc45)ncnc3[nH]2)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)N1CC=C(c2cc3c(Nc4cccc5ccccc45)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension containing naphthalen-1-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine (120 mg, 0.35 mmol), tert-butyl isocyanate (35 mg, 0.35 mmol) and N,N-diisopropylethylamine (122 μL, 0.70 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred overnight at rt. The reaction mixture was poured into saturated NaHCO3 solution (50 mL) and extracted with EtOAc (3×50 ml). The combined organics were washed with brine (3×50 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (2 to 4% MeOH in DCM) gave the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.13 (1H, s), 8.08-8.02 (2H, m), 7.89 (1H, d, J=8.1 Hz), 7.74-7.71 (1H, m), 7.63-7.54 (3H, m), 6.55 (1H, d, J=8.3 Hz), 6.43 (1H, s), 5.83 (1H, s), 4.04 (2H, s), 3.55 (2H, t, J=5.6 Hz), 2.42 (2H, s), 1.34 (9H, s); MS (ES+): m/z 441.08 [MH+], HPLC: tR=2.59 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[O:59])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)ncn4CCC)cc2)CCCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)ncn4CCC)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (300 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-per-benzoic acid (117 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added with vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated aqueous brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (hexane:ethyl acetate=1:4 ethyl acetate) to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (230 mg) as yellow amorphous material (Compound 37).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([NH2:8])=[N:3]1.CC(C)([O-])C.[Na+].[CH3:15][S:16][C:17]1[N:22]=[C:21](SC)[C:20]2=[N:25][CH:26]=[C:27]([C:28]#[N:29])[N:19]2[N:18]=1>C1COCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([NH:8][C:21]2[C:20]3=[N:25][CH:26]=[C:27]([C:28]#[N:29])[N:19]3[N:18]=[C:17]([S:16][CH3:15])[N:22]=2)=[N:3]1
Reactant: CSc1nc(SC)c2ncc(C#N)n2n1
Reactant: Cc1nc(N)nn1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Nc2nc(C)n(C)n2)c2ncc(C#N)n2n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1,5-dimethyl-1H-1,2,4-triazol-3-amine (170 mg, 1.517 nmmol) was taken up in 6 ml of anhydrous THF and cooled to 0° C. Sodium tert-butoxide (243 mg, 2.53 mmol) was added and the reaction was stirred at 0° C. for 5 min. Next, a solution of 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate (300 mg, 1.264 mmol) in 8 ml of THF was added, and the reaction was brought to rt. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the material was dissolved in EtOAc. The organic layer was washed once with water, and the aqueous layer was re-extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (157 mg) as a yellow solid. The crude material was taken onto the next step without further purification.