Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([NH2:14])=[CH:7]2.Cl[C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CC(O)C>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([NH:14][C:16]1[N:21]=[C:20]([NH:14][C:8]3[CH:9]=[N:10][C:11]4[C:6]([CH:7]=3)=[CH:5][C:4]([OH:3])=[CH:13][CH:12]=4)[CH:19]=[CH:18][N:17]=1)=[CH:7]2
Reactant: Nc1cnc2ccc(O)cc2c1
Reactant: Clc1ccnc(Cl)n1
Agent: Br
Solvent: CC(C)O
Product: Oc1ccc2ncc(Nc3ccnc(Nc4cnc5ccc(O)cc5c4)n3)cc2c1
Temperature: 25 °C

Procedure:
A mixture of 6-hydroxy-3-aminoquinoline di-hydrobromide (0.064 g, 0.2 mmol) and 2,4-dichloropyrimidine (0.148 g, 1 mmol) in IPA (1 mL) was heated at reflux overnight. The reaction was cooled to RT and a yellow solid was filtered off and washed with IPA. The solid was purified by flash chromatography in CH2Cl2/MeOH/NH4OH (90/10/1). The fractions containing the compound were combined and the solvents were removed under vacuum. The residue was purified by reverse-phase preparative HPLC (CH3CN/water/TFA) to give the bis-trifluoroacetate of the title compound as a yellow solid. MS (MH+)=397.2, Calc'd for: C22H16N6O2—396.4.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)[CH:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[O:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:40]([C:39]4[CH:38]=[CH:37][C:36]([C:34]([NH:33][C:30]5[CH:29]=[CH:28][C:27]([N:24]6[CH2:23][CH2:22][O:21][CH2:26][CH2:25]6)=[CH:32][CH:31]=5)=[O:35])=[CH:43][CH:42]=4)[NH:18][C:11]=3[CH:10]=2)[CH:3]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Reactant: Cc1cc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)no1
Product: Cc1cc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)[nH]c3c2)no1

Procedure:
Compound 629 was prepared according to the procedure similar to that described in Scheme III from 1-(5-methylisoxazol-3-yl)methoxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C29H27N5O4: 510.21; found: 510.06.
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=1>>[S:15]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:19]1[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=1
Reactant: Brc1cc2c(s1)-c1ccccc1OCC2
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: c1ccc2c(c1)OCCc1cc(-c3ccncc3)sc1-2

Procedure:
2-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine from Example 73 was reacted with 4-pyridine boronic acid pinacol ester using standard Suzuki coupling procedure. Purification on silica gave 153. 1H NMR (400 MHz, CDCl3): 3.29 (2H, t), 4.39 (2H, t), 7.06-7.11 (2H, m), 7.22 (1H, dt), 7.28 (1H, s), 7.49 (2H, dd), 7.75 (1H, dd), 8.62 (2H, dd). MS: (ESI+) 280
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH2:9][C:10]2[S:14][C:13]([CH:15]=[O:16])=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[Na+]>C(O)C>[C:3]1([CH2:9][C:10]2[S:14][C:13]([CH2:15][OH:16])=[CH:12][CH:11]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(Cc2ccccc2)s1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Cc2ccccc2)s1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
Sodium borohydride pellets, 5.6 grams (0.15 mole), were added portionwise during 0.5 hour to a stirred, cooled, solution of 30.0 grams (0.15 mole) of 5-(phenylmethyl)thiophene-2-carboxaldehyde in 400 ml of ethanol. Cooling was continued until the sodium borohydride had completely dissolved. The reaction mixture was then heated at reflux for 0.75 hour, cooled, and concentrated under reduced pressure to give a residual oil. The oil was slurried in ice-water saturated with sodium chloride, and the mixture was extracted with three portions of 150 ml each of chloroform. The extracts were combined, then dried with magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a residual oil. The oil was distilled under reduced pressure using a Kugelrohr distilling system to give 22.5 grams of 5-(phenylmethyl)thiophene-2-methanol; b.p. 106° C./0.2 mm.
Reaction SMILES: BrC[CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[S-:18][C:19]#[N:20].[K+]>CN(C)C=O>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([S:18][C:19]#[N:20])[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Reactant: N#C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(SC#N)C2
Temperature: 100 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
A mixture of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (0.882 g), potassium thiocyanate (2.915 g) and dimethylformamide (40 ml) was stirred in a hot bath at 100° C. for 5 hours. The solvent was distilled off under reduced pressure. The residue was combined with water and extracted with chloroform. The chloroform extract liquid was washed with water, dried and condensed. The residue was crystallized from chloroform--n-hexane to obtain 0.683 g of the title compound as white powder (mp.: 227°-229° C. (dec.)).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2([CH2:9][C:10](=O)[CH3:11])[CH2:7][CH2:8][CH:3]1[CH2:4][CH2:5]2.C(O)(=O)C.[CH3:18][NH2:19]>[Pt]=O.C(O)C>[CH3:18][NH:19][CH:10]([CH3:11])[CH2:9][C:6]12[C:2]([CH3:13])([CH3:1])[CH:3]([CH2:8][CH2:7]1)[CH2:4][CH2:5]2
Reactant: CC(=O)CC12CCC(CC1)C2(C)C
Reactant: CN
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(C)CC12CCC(CC1)C2(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7,7-dimethyl-1-(2-oxo-n-propyl) norbornane (4.69 g), glacial acetic acid (10 ml), methylamine (10g) and ethanol (100 ml) was heated under reflux for 1 hour, cooled to room temperature and hydrogenated for 4 hours at 4 atmospheres using platinum oxide (0.25 g) as catalyst. The catalyst was removed by filtration and the filtrate evaporated to low volume before extracting with ether. The aqueous phase was basified with 2N-sodium hydroxide solution and the liberated base extracted into ether. The combined extracts were washed with water, dried (MgSO4) and evaporated in vacuo to yield the title product (4.15 g) which was characterised as the hydrochloride salt.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2[CH3:21])(=[O:10])=[O:9])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Cl>O1CCOCC1>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:12]=2[CH3:21])(=[O:9])=[O:10])[CH2:7]1
Reactant: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-dimethylethyl (2S)-2-methyl-4-{[2-methyl-5-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 26) (2.1 g, 4.97 mmol) in 1,4-Dioxane (50 mL) was treated by 4 M HCl in dioxane (6.21 mL, 24.85 mmol). The reaction mixture was stirred overnight at room temperature. LCMS showed a 1:1 ratio between starting material and expected product. 4 M HCl in dioxane (6.21 mL, 24.85 mmol) was added and the reaction mixture stirred for 4 h. LCMS showed about 10% of remaining starting material. 4 M HCl in dioxane (6.21 mL, 24.85 mmol) was added and the reaction mixture stirred for 1 h.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=O)(C)(C)C.O1CCOCC1.Cl>CO>[F:13][C:11]1([F:14])[CH2:12][NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (500 mg, 1.99 mmol) in methanol (30 mL) was added 4N HCl dioxane (3 mL). The reaction mixture was stirred at rt for 6 h. Concentration gave an oil which was used for the next step without purification (480 mg, 100%). 1H NMR (CD3OD, 400 MHz) δ 4.76 (1H, t, J=8.5 Hz), 3.79-3.87 (2H, m), 2.91-3.03 (1H, m), 2.73-2.82 (1H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=1.C(N(CC)CC)C.[CH2:31]([NH:34][C:35](=[O:42])[CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[C:32]#[CH:33]>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>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][CH2:8][N:6]3[C:5](=[O:23])[CH:4]=[CH:3][C:2]([C:33]#[C:32][CH2:31][NH:34][C:35](=[O:42])[CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:7]3)=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: C#CCNC(=O)CN1CCCC1
Reactant: COc1ccc2c(OCCn3cc(Br)ccc3=O)ccnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(OCCn3cc(C#CCNC(=O)CN4CCCC4)ccc3=O)ccnc2c1
Yield: 21.7 %

Procedure:
To a 50 mL round bottom flask was charged with the 5-bromo-1-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1H)-one (0.136 g, 0.4 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.005 g, 0.007 mmol), and copper(I) iodide (0.0002 ml, 0.007 mmol) along with a magnetic stirring bar and degassed and back-filled three times with N2. Triethylamine (0.2 ml, 1 mmol) was introduced into the reaction flask using a syringe under the gaseous mixture atmosphere. Then N-(prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide (0.06 g, 0.4 mmol) was added to the reaction flask. After refluxing for 16 hours, the solvent was evaporated and the residue was shaken with 20 mL of saturated aqueous sodium bicarbonate solution and 50 mL of EtOAc. The organic layer was washed with 20 mL of brine and then dried over anhydrous sodium sulfate. The organic solution was concentrated in vacuo and the residue was purified by a Prep-HPLC to give a yellow solid (0.04 g, 24% yield). MS (ESI pos. ion) m/z (MH+): 461.1. Calc'd Exact Mass for C26H28N4O4: 460.21.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([NH:22][CH3:23])[CH2:20][CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C>CC1C=CC=CC=1C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([NH:22][CH3:23])=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:24][CH:25]=1
Reactant: CNC1CCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Temperature: 156 °C

Procedure:
To a solution of N-(4-fluorobenzyl)-3-hydroxy-9-(methylamino)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide hydrotrifluoroacetate and diisopropylethylamine (4 eqs.) in o-xylene was added Pd(C) (10%). The suspension was stirred and heated to 156° C. for 7 hours. The suspension was left cooling to room temperature and the catalyst was filtered off. The catalyst was washed with methanol and dichloromethane and the filtrate and catalyst washes were combined and the combined organic solutions were concentrated to dryness. The product was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluants (column: C18). After lyophilization of the pooled product fractions the product was obtained as bright yellow fluffy material.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:54]([C:56]1[CH:62]=[CH:61][C:59]([NH2:60])=[CH:58][CH:57]=1)[CH3:55].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:60][C:59]3[CH:61]=[CH:62][C:56]([CH2:54][CH3:55])=[CH:57][CH:58]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: CCc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (63 mg, 0.165 mmol) in 1.5 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 10 minutes 4-ethylaniline (0.028 mL, 0.225 mmol) was added and the reaction stirred at room temperature for 4 hours, then allowed to stand at room temperature overnight. The reaction was added drop wise to a stirring mixture of 35 mL water containing 4 mL brine and 0.3 mL saturated aqueous Na2CO3 solution at room temperature. The resulting precipitate was filtered and rinsed with water. The damp solid was dissolved in 40% MeOH in CHCl3 and evaporated to a dry solid. The solid was triturated with an acetone/hexane mixture to give the title compound as a light beige solid (48 mg, 86%). 1H NMR (DMSO-d6) δ: 10.08 (s, 1H), 8.13 (s, 1H), 7.63-7.69 (m, 2H), 7.50 (s, 1H), 7.31-7.40 (m, 2H), 7.15-7.24 (m, 3H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 2.58 (q, J=7.5 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][NH2:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:13]([CH:15]([CH:20]=O)[C:16]([O:18][CH3:19])=[O:17])=O>CCO>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[N:12]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NNc1ccc2ncc(Br)n2n1
Reactant: COC(=O)C(C=O)C=O
Solvent: CCO
Product: COC(=O)c1cnn(-c2ccc3ncc(Br)n3n2)c1
Temperature: 70 °C

Procedure:
A mixture of 3-bromo-6-hydrazinylimidazo[1,2-b]pyridazine (866 mg, 3.8 mmol) and methyl 2-formyl-3-oxopropanoate (500 mg, 3.8 mmol) in EtOH (20 mL) was heated at 70° C. overnight. The mixture was concentrated and treated with MeOH. The titled compound (410 mg) was collected by filtration. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.94 (s, 3H) 7.84 (s, 1H) 8.01 (d, J=9.60 Hz, 1H) 8.11 (d, J=9.60 Hz, 1H) 8.19 (s, 1H) 9.09 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:49])([O:4]/[N:5]=[C:6](/[C:23]1[N:24]=[C:25]([NH:28]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:26][CH:27]=1)\[C:7]([O:9]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])[CH3:3]>C(O)=O>[NH2:28][C:25]1[S:26][CH:27]=[C:23](/[C:6](=[N:5]/[O:4][C:2]([CH3:3])([C:48]([O:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=2)=[O:49])[CH3:1])/[C:7]([OH:9])=[O:8])[N:24]=1
Reactant: CC(C)(O/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O=CO
Product: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Diphenylmethyl (Z)-2-[1-methyl-1-(4-nitrobenzyloxy-carbonyl)ethoxyimino]-2-(2-tritylaminothiazol-4-yl)-acetate (1.0 g) was treated with formic acid under the conditions described in Example 23d. The title compound was obtained as a white solid (0.355 g, 75%); νmax (Nujol) 3300 (br), 3100 (br), 1740, 1625 (br). 1610, 1520, and 1350 cm-1 ; δH ((CD3)2SO) 1.50 (6H, s), 5.30 (2H, s), 6.74 (1H, s), 7.15-7.40 (3H, m), and 7.59 and 8.08 (4H, ABq, J 9 Hz).
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH:4]([C:11](Cl)([CH3:13])[CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].CC(C)([O-])C.[Na+].Cl>CN(C)C=O>[CH3:12][C:11]1([CH3:13])[CH:4]([CH:3]=[C:2]([Cl:15])[Cl:1])[CH:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C=C(Cl)Cl)C(C)(C)Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Yield: 90 %

Procedure:
A solution of 274 g (1 mole) ethyl 3-(2,2-dichlorovinyl)-4-chloro-4-methyl-pentanoate in 1.5 liter of dry dimethylformamide (DMF) was cooled to 0° C. A suspension of 101 g (1.05 mole) sodium t-butoxide in 1 liter dry DMF was added to the solution over a period of 2 hours. The reaction mixture was then neutralized with dry HCl. The DMF was distilled off under vacuum to give a 90% yield of ethyl 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropane carboxylate. B.p. 85°-95° C./0.2-0.3 mm Hg.
Reaction SMILES: C(OC(=O)[N:7]([CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[NH:22])=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)(C)(C)C.Cl>CO>[CH:28]([NH:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[NH:22])=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)([CH3:30])[CH3:29]
Reactant: CC(C)N(CCN1CCCc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)NCCN1CCCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C

Procedure:
A solution of tert-butyl-isopropyl(2-(6-(thiophene-2-carboximidamido)-3,4-dihydro-quinolin-1(2H)-yl)ethyl)carbamate (compound 6, 50 mg, 0.113 mmol) in HPLC grade methanol (10 mL) was treated with 2N aq. HCl (0.565 mL, 1.13 mmol) and the mixture heated to reflux for 2 hours then cooled to room temperature overnight. The solution was concentrated and dried briefly on high-vac pump. The residue was taken up in 7.5% 2M NH3 in methanol/92.5% dichloromethane (5 mL), reconcentrated then purified directly on silica gel eluting with 7.5% 2M NH3 in methanol/92.5% dichloromethane to yield a yellow solid, 61 (40 mg, quantitative). 1H-NMR (DMSO-d6) δ 7.66 (d, 1H, J=3.1 Hz), 7.54 (d, 1H, J=5.1 Hz), 7.06 (dd, 1H, J=5.0, 3.7 Hz), 6.61-6.50 (m, 2H), 6.47 (br s, 1H), 6.21 (br s, 2H), 3.30-3.18 (m, 4H), 2.79-2.70 (m, 1H), 2.70-2.61 (m, 4H), 1.88-1.80 (m, 2H), 0.97 (d, 6H, J=6.2 Hz). MS (ESI+): 343 (MH+, 100); ESI-HRMS calculated for C19H27N4S (MH+): 343.1950; observed: 343.1953.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.[CH3:11]C1C(C)=C(C)N=C(O)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH3:11])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(O)nc(C)c1C
Reactant: Cc1nc(Cl)nc(C)c1C
Product: CCc1c(C)nc(Cl)nc1C

Procedure:
The title compound was prepared in a manner analogous to Intermediate 66, substituting 5-ethyl-4,6-dimethylpyrimidin-2-ol for 4,5,6-trimethylpyrimidin-2-ol. MS (ESI): mass calculated for C8H11ClN2, 170.06, m/z found 171.1 [M+1]+. 1H NMR (500 MHz, CDCl3): 2.65 (q, J=7.6 Hz, 2H), 2.50 (s, 6H), 1.15 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1.[I-].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (50 mg, 0.133 mmol) was added to a suspension of sodium hydride (7.99 mg, 0.200 mmol) in DMF (Volume: 2 ml). The reaction was allowed to stir for 10 minutes at 60° C. 1-(chloromethyl)-4-nitrobenzene (45.7 mg, 0.266 mmol) and potassium iodide (44.2 mg, 0.266 mmol) were added and the reaction was stirred overnight at 60° C. The reaction was diluted with water and ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered and concentrated. The crude material was purified using 40-100% ethyl acetate:hexanes to afford the product as a white solid. (Yield: 11 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 8.20-8.12, 7.70-7.62, 7.55, 7.43-7.08, 6.81-6.75, 5.71-5.61, 4.62, 4.56-3.95, 3.21-2.85, 2.74, 1.81-1.13
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH2:3][C:4]([OH:6])=[O:5].Cl.[CH3:16][CH2:17]O>>[CH2:16]([O:5][C:4](=[O:6])[CH2:3][C@H:2]([NH2:1])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH3:17]
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1Cl
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C[C@H](N)Cc1ccccc1Cl

Procedure:
(R)-3-Amino-4-(2-chloro-phenyl)-butyric acid (10 g, 50 mmol) was dissolved in absolute EtOH (250 mL). Concentrated HCl (2 mL) was added and the mixture was heated to reflux overnight. The product was vacuumed to dryness and azeotroped with toluene (4×50 mL), then placed under high vacuum overnight to yield the title compound as a white solid (10 g).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=1.[C:30](#[N:33])[CH:31]=[CH2:32].CCN(C(C)C)C(C)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH2:23]([O:22][C:17]1[C:16]2[N:15]([N:14]=[CH:32][C:31]=2[C:30]#[N:33])[CH:20]=[C:19]([Cl:21])[N:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=CC#N
Reactant: N[n+]1cc(Cl)nc(OCc2ccccc2)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnn2cc(Cl)nc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
1-amino-3-(benzyloxy)-5-chloropyrazin-1-ium 2,4,6-trimethylbenzenesulfonate (5.34) (657 mg, 1.51 mmol) was suspended in 1,4-dioxane (5.75 mL) and acrylonitrile (0.23 mL, 3.5 mmol) was added followed by iPr2NEt (0.32 mL, 1.9 mmol). The resulting mixture was stirred for 1.75 h at r.t. and DDQ (720 mg, 3.2 mmol) was added in one portion. The resulting mixture was stirred an additional 1 h and was then partitioned between EtOAc, water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (0-20% EtOAc in hexanes) to provide 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carbonitrile. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 8.18 (s, 1H), 7.61-7.55 (m, 2H), 7.45-7.39 (m, 2H), 7.39-7.33 (m, 1H), 5.67 (s, 2H).
Reaction SMILES: [CH:1](=[N:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(COC)OC>[CH3:13][N:12]([CH3:14])[S:9]([N:8]1[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:26][N:25]=[CH:24]1)(=[O:11])=[O:10]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)S(=O)(=O)N=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: CN(C)S(=O)(=O)n1cncc1-c1ccccc1

Procedure:
N-Benzylidene-N',N'-dimethylsulphamide (6.36 g) was stirred with p-toluenesulphonylmethyl isocyanide (9.75 g ) and potassium carbonate (8.28 g) in methanol and dimethoxyethane for 18 hours. The mixture was filtered and the filtrate evaporated and recrystallised from ethyl acetate/hexane to give crude 1-dimethylsulphamoyl-5-phenylimidazole.