Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:20][C@H:21]([OH:37])[C@@H:22]([NH:30]C(=O)C(F)(F)F)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][CH:13]=1>CO>[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:20][C@H:21]([OH:37])[C@@H:22]([NH2:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
55 ml of a 1N K2CO3 solution are added dropwise to 3.12 g (5.5 mmol) of 1-[4-(thiazol-2-yl)phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane in 55 ml of methanol and the mixture is stirred at 70° C. for 9 hours. The mixture is cooled and ≈30 ml of methanol are evaporated off; methylene chloride and water are added and the aqueous phase is separated off and extracted with methylene chloride; the organic phases are washed with water, dried (Na2SO4) and concentrated by evaporation, yielding the title compound: HPLC20-100 : tRet =11.9; FAB MS (M+H)+ =469.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[CH3:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH2:34])=[NH:33])[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:33]=[C:32]([NH:31][C:26]4[CH:25]=[C:24]([CH3:23])[CH:29]=[C:28]([CH3:30])[CH:27]=4)[N:34]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: Cc1cc(C)cc(NC(=N)N)c1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: Cc1cc(C)cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3,5-dimethyl-phenyl)-guanidine nitrate were converted to I-35 (71%): HRMS Calcd. for C20H17ClN40: 365.1169, Found 365.1190.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[F:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][CH:47]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13]([N:55]3[CH2:54][CH2:53][N:52]([C:49]4[CH:48]=[CH:47][C:46]([F:45])=[CH:51][CH:50]=4)[CH2:57][CH2:56]3)=[O:14])=[O:18])[CH2:20][CH2:21]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCN(c3ccc(F)cc3)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and N-(4-fluorophenyl)piperazine (38.0 mg, 2.0 equiv) in dimethylformamide (0.50 mL) and dichloromethane (0.50 mL) at 0° C. was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0° C. for 4 h. The reaction was concentrated and purified by column chromatography (95:5:1 to 90:10:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanoudichloromethane and passed through a basic alumina column to give 71.2 mg (quant.) as a white powder. 1H-NMR (CD3OD, 500 MHz) δ 1.25-1.75 (m, 2H), 1.75-2.25 (m, 9H), 2.51 (s, 3H), 2.75 (m, 1H), 2.75-3.30 (m, 13H), 3.48 (m, 3H), 3.80 (m, 1H), 4.05-4.50 (m, 2H), 5.55 (dd, J=7.6, 7.3, 1H), 6.68 (m, 2H), 6.91 (m, 1H), 7.11 (s, 1H), 7.21 (dd, J=7.9, 7.3, 1H), 7.32 (d, J=8.2, 1H), 7.47 (dd, J=7.9, 7.3, 1H), 7.51 (m, 1.5H), 7.61 (d, J=7.6, 1H), 7.67 (bs, 0.5H), 8.00 (s, 1H). Mass spec.: 637.28 (MH)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[K+].[CH:14]([B-](F)(F)F)=[CH2:15]>>[CH:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)=[CH2:15]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: [K+]
Product: C=Cc1ccc(C(=O)OC)c(F)c1

Procedure:
The title compound was prepared from methyl 4-bromo-2-fluorobenzoate and vinyltrifluoroborate potassium salt according to the procedure for the preparation of Example 135, part A. 1H NMR (300 MHz, CDCl3): δ 3.92 (3H, s), 5.43 (1H, d, J=11.1 Hz), 5.86 (1H, d, J=17.4 Hz), 6.69 (1H, dd, J=11.1 Hz, 17.4 Hz), 7.15 (1H, d, J=12.0 Hz), 7.21 (1H, dd, J=0.9 Hz, 7.8 Hz), 7.89 (1H, t, J=8.1 Hz).
Reaction SMILES: Br.[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12]C)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O)CO.O.[NH2:19]N>O>[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][NH2:19])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1nc2c(C)cccc2s1
Reactant: NN
Agent: Br
Solvent: OCCO
Solvent: O
Product: Cc1cccc2sc(NN)nc12
Yield: 90 %

Procedure:
4-Methyl-2-methylaminobenzothiazole hydrobromide (443 g.; 1.71 mole) was added with stirring to 1.7 liter of ethylene glycol. 85% Hydrazine hydrate (400 grams; 6.75 mole) was added in several portions. The reaction mixture was heated to 130°-135°C. under N2 atmosphere and maintained for about four hours, then cooled slowly with stirring. The product was isolated by addition of water and separated by filtration. It was then dried overnight in a vacuum oven, yielding 275.5 g. (90% yield) of 4-methyl-2-hydrazinobenzothiazole. The nmr spectrum agreed with a reference spectrum and showed no evidence of starting material or other impurity. Non-aqueous titration showed the product to be 97.5% pure.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:3][CH:2]=1.Cl.O1CCOCC1.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>ClCCl>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:38](=[O:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Reaction time: 0.75 h
Yield: 36.1 %

Procedure:
To (R)-tert-butyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (26.4 mg, 0.064 mmol) is added 4M HCl in 1,4-dioxane (0.321 ml, 1.283 mmol) at room temperature. The reaction mixture is stirred for 45 minutes and concentrated under reduced pressure. To a solution of the obtained residue in dichloromethane (0.4 mL) is added succinic anhydride (7.70 mg, 0.077 mmol) and DIPEA (0.013 mL, 0.077 mmol). The reaction mixture is allowed to stir at room temperature for 14 hours and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C-18, H2O (0.1% TFA)/CH3CN) to give (R)-4-(1-(biphenyl-4-yl)-4-tert-butoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (9.5 mg). HPLC retention time=1.70 minutes (condition A); MS (ES+)=412.1 (m+1); 356.0 (m-tBu+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9 H) 2.36-2.51 (m, 4 H) 2.64-2.67 (m, 2 H) 2.87 (A of ABX, Jab=13.5 Hz, Jax=5.7 Hz, 1 H), 2.97 (Jab=13.5 Hz, Jbx=6.2 Hz, 1 H) 7.24-7.26 (m, 2 H) 7.31-7.35 (m, 1 H) 7.43 (t, J=7.75 Hz, 2 H) 7.53(d, J=8.0 Hz, 2 H) 7.57 (d, J=7.6 HZ, 2 H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][C:31]=1[OH:37].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][C:31]=1[O:37][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28]
Reactant: Cc1cc(C)c(O)cn1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2cnc(C)cc2C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 4,6-dimethylpyridin-3-ol (0.19 g), 8 M potassium hydroxide solution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.4 g, 80%).
Reaction SMILES: [CH2:1]([C@:8]1([C:23]([NH:25][CH2:26][CH:27]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)[OH:28])=[O:24])[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([C@:8]1([C:23]([NH:25][CH2:26][C:27]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[CH:30]=2)=[O:28])=[O:24])[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)cc(C(O)CNC(=O)[C@@]2(Cc3ccccc3)OC(=O)N([C@H](C)c3ccccc3)C2=O)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)CNC(=O)[C@@]2(Cc3ccccc3)OC(=O)N([C@H](C)c3ccccc3)C2=O)c1
Reaction time: 0.5 h

Procedure:
To the product from Step A (310 mg, 0.598 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (392 mg, 0.897 mmol) and the mixture was stirred for 30 min. A 1:1 mixture of saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate (20 mL) was added and the mixture was stirred rapidly for 15 min. The layers were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic phases were washed with saturated aqueous brine (1×15 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo, to afford the crude colorless title compound as an amorphous solid. LC/MS 517.1 (M+1).
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:63][CH3:64])[N:32]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50](C(OCC2C=CC=CC=2)=O)[CH2:49][CH2:48]1>>[CH2:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:63][CH3:64])[N:32]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:48][CH2:49][NH:50][CH2:51][CH2:52]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{5-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]pentyl}-1-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A 2 L flask was charged the solution of 4-chloro-1-methyl-2-nitrobenzene (60 g, 0.35 mol) in MeOH (1 L), Raney Ni was added, the air in flask was replaced three times with H2, the mixture was stirred for 3 hr at rt. The solution was filtered and concentrated. The residue was dissolved in CH2Cl2 (500 mL), and the solution was washed with brine, dried over Na2SO4. Solvent removal gave 5-chloro-2-methylbenzenamine (50 g, 0.35 mol). 1H NMR (CDCl3, 400 MHz) δ 7.02-6.93 (d, 2H), 6.70-6.60 (d, 2H), 3.67 (s, 2H), 2.14 (s, 3H).
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:5]1[C:4]2[CH:3]=[CH:2][O:1][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]ccc2occc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2occc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
5H-Furo[3,2-c]pyridin-4-one (5.9 g) was suspended with POCl3 (12 ml) and the reaction mixture was stirred for 3 hours at 120° C. After evaporating POCl3, crushed ice was added and poured into the mixture of ethyl acetate and saturated NaHCO3. The corresponding organic phase was separated and dried over Na2SO4 and then concentrated in vacuo. The resultant residue was purified by chromatography on a silica gel column to afford 4-chloro-furo[3,2-c]pyridine (5.6 g) 1H NMR (400 MHz, DMSO-d6) ppm 8.31 (d, J=5.8 Hz, 1H), 8.26 (d, J=2.3 Hz, 1H), 7.79 (dd, J=1.0, 5.6 Hz, 1H), 7.13 (dd, J=1.0, 2.3 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: NCCC(=O)O
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)CCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 100.1 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and β-alanine (0.46, 0.0052 mol) were refluxed as above for 7 hours. Crystallisation of the product from EtOH yielded 1.37 g (78%) of 101 as a white solid: mp=240-242° C.; Rf0.77 (A): Rf0.67 (B): Rf0.33 (D): 1H NMR (DMSO-d6); MS m/z (rel intensity) 263 (14), 262 (100); IR (cm−1): 2800-3250 (OH), 1350 (C═CH), 2671 (C—H), 1777 (C═O), 1725 (C═O), 1705 (C═O), 1620 (C═C), 1452 (C═C), 1385(C—O), 1226 (C—O), 731 (C═CH). MS m/z (rel intensity) 263 (14), 262 (100).
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].P(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1[NH:4][C:5]([CH3:13])=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:2]=1
Reactant: COc1ccccc1-c1nc(C)c(-c2cccnc2)n1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Solvent: O
Product: COc1ccccc1-c1nc(-c2cccnc2)c(C)[nH]1
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a solution of 1-hydroxy-2-(2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.5 g) in N,N-dimethylformamide (10 ml) was added phosphorus trichloride (0.31 ml) under ice-cooling. The mixture was stirred for 2 hours at 5° to 10° C. The mixture was poured into water (100 ml), and neutralized with aqueous sodium bicarbonate. The precipitate was collected, washed with water, and dried to give 2-(2-methoxyphenyl)-5-methyl-4-(3-pyridyl)imidazole (0.31 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CN([CH:28]=[O:29])C>>[C:1]1([C:7]2[N:8]=[C:9]([CH:28]=[O:29])[N:10]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1cc(-c2ccccc2)nc1C=O
Yield: 97.8 %

Procedure:
Reaction of 4-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (380 mg, 1.39 mmol), 2.5 M n-BuLi (720 uL, 1.80 mmol), and DMF (323 uL, 4.17 mmol) for 4 h at −40° C. gave the title compound (411 mg, 98%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.93 (t, 2H, J=9.0 Hz), 3.61 (t, 2H, J=9.0 Hz), 5.83 (s, 2H), 7.26–7.46 (m, 3H), 7.65 (s, 1H), 7.83 (d, 2H, J=9.0 Hz), 9.89 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[OH-].[K+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH3:22])([S:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][CH:7]=1)[CH3:21])[CH3:20]
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Sc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a stirred solution of 10 g (56 mmol) of 4-trifluoromethylbenzene-1-thiol in ethanol (100 mL) were added 3.14 g (56 mmol) KOH pellets, followed by 10.95 g (56 mmol) ethyl α-bromoisobutyrate. The reaction mixture was heated to reflux for 18 h. The reaction was cooled to room temperature. The solid (KBr) was separated by filtration and rinsed with ethanol (20 mL). The filtrate was concentrated under reduced pressure and the residue dissolved in DCM (60 mL). The organic layer was washed with water (2×30 mL). The aqueous washes were back-extracted with DCM (15 mL). The combined organics were washed with brine and dried over Na2SO4. Filtration and concentration under reduced pressure afforded 16.3 g of 2-methyl-2-(4-trifluoromethyl-phenylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C.CO.O>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:7]1
Reactant: CN1CCC(=NNC(=O)OC(C)(C)C)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(NNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of tert-butyl 2-(1-methylpiperidin-4-ylidene)hydrazinecarboxylate (500 mg, 2.20 mmol) in THF (50 mL) was added DIBAl-H (22 mL, 22 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 25° C. overnight. Methanol (5 mL) was added to quench the reaction at −78° C. After being stirred at room temperature for 1 h, water (10 mL) was added. The solid was filtered off and washed with EtOAc. The combined filtrate was partitioned and extracted with EtOAc (3×50 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:10) to give tert-butyl 2-(1-methylpiperidin-4-yl)hydrazinecarboxylate (350 mg, 69% yield) as a colorless oil. LCMS (ESI) m/z: 230.4 [M+H+].
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[C:10](=[O:29])[N:11]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)[C:12]2=[O:17])C1C=CC=CC=1.C(OCC)(=O)C>[Pd].C(O)C>[F:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([N:11]2[C:12](=[O:17])[CH:13]3[NH:8][CH:9]([CH2:16][CH2:15][CH2:14]3)[C:10]2=[O:29])=[CH:19][CH:20]=1
Reactant: O=C1C2CCCC(C(=O)N1c1ccc(OC(F)(F)F)cc1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1C2CCCC(N2)C(=O)N1c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h

Procedure:
A mixture of 9-benzyl-3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione (120 mg, 0.3 mmol), 10% Pd/C (20 mg, 0.02 mmol Pd), ethyl acetate (8 mL), and ethanol (2 mL) were stirred vigorously under an atmosphere of H2. After 2 h, more ethanol (2 mL) was added. After an additional 16 h, the reaction was filtered through Celite and concentrated to give 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione: MS (ESI): 315.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C>CN(C=O)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>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2](/[CH:25]=[CH:24]/[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: C=CS(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(/C=C/S(C)(=O)=O)cc1-2
Yield: 73.1 %

Procedure:
A mixture of 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (0.36 g, 0.92 mmol), methyl vinyl sulfone (0.24 mL, 2.8 mmol), bis(triphenylphosphine)palladium(II) chloride (64 mg, 0.092 mmol) and triethylamine (0.64 mL, 4.6 mmol) in DMF (10 mL) was heated under an argon atmosphere for 16 h. The reaction mixture was concentrated and purified by column chromatography (40 g column, 0-100% EtOAc/heptane) to provide 280 mg (73% yield) of 143. LC/MS (ESI+): m/z 417 (M+H). 1H NMR (400 MHz, DMSO) δ 8.59 (d, J=2.0, 1H), 8.11 (s, 1H), 7.71 (dd, J=8.4, 2.1, 1H), 7.59-7.26 (m, 2H), 7.17 (d, J=8.4, 1H), 5.88-5.67 (m, 1H), 4.43 (t, J=4.8, 2H), 3.48 (dd, J=12.3, 7.5, 2H), 3.12 (s, 1H), 1.58 (d, J=6.6, 6H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[CH:4][C:3]=1[CH3:17].C1(C2(CC(O)(C)C)OC(=O)N([C@H](C3C=CC(C4C=CN(C)C(=O)C=4)=CC=3)C)CC2)CC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[CH:4][C:3]=1[CH3:17]
Reactant: CC(=N[S@](=O)C(C)(C)C)c1ccc(Br)c(C)c1
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Product: Cc1cc([C@H](C)N[S@](=O)C(C)(C)C)ccc1Br

Procedure:
The title compound was prepared from (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-3-methyl-phenyl)-ethylidene]-amide following a procedure analogous to that described in Step 2 of Intermediate 1. LC-MS (Method 5): tR=4.04 min; Mass spectrum (ESI+): m/z=318/320 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[C:18](O)=[O:19])([CH3:12])[CH3:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:18]([C@@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[CH:10]([CH3:12])[CH3:11])=[O:19])[NH2:9])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)N1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)N1CCC[C@H]1C(=O)N(N)c1ccc(F)cn1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (200 mg, 1.57 mmol) in DMF (15.0 mL) was added (5)-1-isopropyl-pyrrolidine-2-carboxylic acid (Chem. Commun. 2006, 14, 1482, which is incorporated herein by reference in its entirety; 247 mg, 1.57 mmol), EDC (332 mg, 1.73 mmol) and HOBt.H2O (20.0 mg, 0.16 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound (346 mg, 83%). LCMS (Method 1): Rt 0.37 min, m/z 267.1 [MH+].