Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12BC(CCC1)CCC2.[Cl:10][C:11]1[C:12]([C:26]2[N:30]([CH2:31][CH:32]=[CH2:33])[N:29]=[N:28][N:27]=2)=[C:13]2[C:18](=[CH:19][C:20]=1[Cl:21])[N:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[N:14]2.C[N+]([O-:38])(C)C>O1CCCC1>[Cl:10][C:11]1[C:12]([C:26]2[N:30]([CH2:31][CH2:32][CH2:33][OH:38])[N:29]=[N:28][N:27]=2)=[C:13]2[C:18](=[CH:19][C:20]=1[Cl:21])[N:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[N:14]2
Reactant: C=CCn1nnnc1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reactant: C[N+](C)(C)[O-]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)c(Cl)c(-c3nnnn3CCCO)c2nc1OC
Yield: 72.7 %

Procedure:
9-Borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran, 9.1 mL, 4.55 mmol) was added dropwise to a stirred suspension of 6,7-dichloro-2,3-dimethoxy-5-(1-allyl-1H-tetrazol-5-yl)quinoxaline (Preparation 19, 0.67 g, 1.82 mmol) in dry tetrahydrofuran (15 mL) at room temperature under nitrogen. The reaction mixture was heated under reflux for 18 hours, trimethylamine-N-oxide (1.03 g, 13.7 mmol) was added portionwise to the cooled reaction mixture and the mixture was heated under reflux for 2 hours then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (100:0 changing to 99.5:0.5, by volume) to give the title compound (0.510 g, 73%) as a white solid, mp 188-189° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2](C)=[CH2:3].Cl[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:14](N(CC)CC)C>>[CH3:14][CH:3]=[CH:2][C:1]([O:6][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5]
Reactant: CCOC(=O)CCl
Reactant: C=C(C)C(=O)O
Reactant: CCN(CC)CC
Product: CC=CC(=O)OCC(=O)OCC
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a flask equipped with a stirrer was added 172.8 parts methacrylic acid and 202 parts triethylamine. This mixture was allowed to stir for 5 min. To this was added 245 parts ethyl chloroacetate. The reactants were heated to 60° C. and the exotherm carried the temperature up to 100° C. The temperature was kept between 90°-97° C. by cooling for 1/2 hour after which heat was supplied to hold the temperature at 90° for 1 hour. The mixture was cooled and filtered. This crude product was distilled at 65.5°-66° C. at 0.1 cm to yield 318 g of pure EMA as confirmed by chemical analysis.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([Cl:15])[CH:13]=2)[N:8]=[C:7]([OH:17])[C:6]=1[C:18]([O:20]CC)=O)=[N+]=[N-].[H][H].C[OH:26]>CN(C)C=O.[Pd]>[Cl:16][C:11]1[C:12]([Cl:15])=[CH:13][C:14]2[C:5]3[C:4](=[O:26])[NH:1][C:18](=[O:20])[C:6]=3[C:7]([OH:17])=[N:8][C:9]=2[CH:10]=1
Reactant: CO
Reactant: CCOC(=O)c1c(O)nc2cc(Cl)c(Cl)cc2c1CN=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c1c(O)nc1cc(Cl)c(Cl)cc21

Procedure:
1.0 g (0.003 mol) of ethyl 4-azidomethyl-6,7-dichloro-2-hydroxy-quinoline-3-carboxylate was dissolved in a mixture of 80 ml of methanol and 20 ml of dimethylformamide and treated with 50 mg of 10% Pd/C. A stream of hydrogen was conducted in slowly during 11/4 hrs. The suspension was suction filtered and the filter cake was suspended in dimethylformamide. The mixture was filtered, concentrated, the residue was suspended in methanol and suction filtered. The substance (0.31 g) was suspended in dimethylformamide and an oxygen stream was conducted in slowly during 2 hrs. The mixture was concentrated and the product was recrystallized from dimethylformamide/methanol. Yield: 0.27 g (20%) of 7,8-dichloro-4-hydroxy-2,3-dihydro-1H-pyrrolo[3,4-c]-quinoline-1,3-dione as yellow crystals; m.p. >350° C.
Reaction SMILES: CN(C)CCCNC(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:51]([C:56]([OH:58])=O)=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH2:65]>C1COCC1>[CH3:59][N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:56]([C:51]1[C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:58]
Reactant: CN(C)CCCCN
Reactant: O=C(O)c1ccccc1-c1ccccc1CSCCOc1ccccc1
Agent: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CN(C)CCCCNC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (4-dimethylamino-butyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (1.0 g, 2.74 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.45 g, 2.79 mmol, 1.02 eq.) and 4-dimethylaminobutylamine (0.35 g, 3.01 mmol, 1.1 eq.). When complete, the reaction was worked up as described leaving a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(S)CC.[Br:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])Br>CN(C)C=O>[Br:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[O:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[Cl:10]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(OC(F)(F)C(F)(F)Br)c(Cl)c1

Procedure:
In a manner similar to Step A of Example 1, the reaction of 12.5 g 0.07 mole) 4-amino-2,6-dichlorophenol, 7.3 g (0.053 mole) potassium carbonate, 1.0 g (0.013 mole) propanethiol, 36.5 g (0.14 mole) 1,2-dibromotetrafluoroethane and 125 ml of N,N-dimethylformamide produced 3.7 g of 4-(2-bromo-1,1,2,2-tetrafluoroethoxy)-3,5-dichloroaniline as an oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17].[CH3:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:24]3[C:23]([CH3:22])=[CH:27][C:26]([CH3:28])=[N:25]3)[N:11]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)c(Cl)c3)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 3,4-di-chloroaniline and 3,5-dimethylpyrazole. Mp. 223.9-226.5° C.
Reaction SMILES: C([O:5]C1C=CC(SC(C2C=CC(Cl)=CC=2)C(NO)=O)=CC=1)C#CC.[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])=[O:37])=[CH:32][CH:31]=1)[C:26]#[C:27][CH3:28]>>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])(=[O:5])=[O:37])=[CH:34][CH:35]=1)[C:26]#[C:27][CH3:28]
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)c2ccc(Cl)cc2)cc1
Reactant: CC#CCOc1ccc(SC(C(=O)NO)c2ccc(Cl)cc2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)c2ccc(Cl)cc2)cc1
Yield: 29 %

Procedure:
Starting from a mixture of 2-{[4-(2-butynyloxy)phenyl]sulfanyl}-2-(4-chlorophenyl)-N-hydroxyacetamide (from example 80) and 2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-(4-chlorophenyl) N-hydroxyacetamide (750 mg, 1.99 mmol), and following the procedure as outlined in Example 75, 228 mg of 2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-(4-chlorophenyl)-N-hydroxyacetamide was isolated as a white solid. mp: 140° C.; Yield: 29%; MS: 394.2 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ1.85 (t, J=2.19 Hz, 3H), 4.86 (d, J=2.28 Hz, 2H), 5.05 (s, 1H), 7.1 (d, 2H), 7.4 (m, 4H), 7.5 (d, 2H), 9.33 (s, 1H), 10.8 (s, 1H).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34](Cl)(=[O:36])=[O:35]>N.CO>[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[S:34]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1cccs1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Thiophene-2-sulfonyl chloride (18 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (10.2 mg). MS m/z 335 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:4][CH:3]=1.[C:21]1([P:27](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:19]1[C:20]2[N:8]([C:6]3[N:7]=[C:2]([P:27](=[O:28])([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:3]=[CH:4][CH:5]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: Brc1cccc(-n2c3ccccc3c3ccccc32)n1
Product: O=P(c1ccccc1)(c1ccccc1)c1cccc(-n2c3ccccc3c3ccccc32)n1

Procedure:
Compound 58 was synthesized from 9-(6-bromo-2-pyridyl)carbazole and diphenylphosphinic chloride as in Synthetic Example 1.
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[N:25]1([C:31](=[S:33])[NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CCO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:32]=[C:31]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[S:33][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Reactant: NC(=S)N1CCCCC1
Solvent: CCO
Product: CC(C)c1nnc2ccc(-c3sc(N4CCCCC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Yield: 39 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.250 g, 0.632 mmol; Preparation #A.2) and piperidine-1-carbothioamide (Oakwood Products Inc., 0.082 g, 0.57 mmol) in EtOH (3 mL) was heated to reflux for about 3 h. After cooling to ambient temperature, the crude mixture was partitioned between DCM and water. The organics were dried over MgSO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using heptane/EtOAc (linear gradient, 50:50 to 0:100) to give the title compound (0.098 g, 35%): LC/MS (Table 1, Method a) Rt=4.18 min; MS m/z: 441.8 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]([OH:21])=O)[C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1.ClC(OCC)=O.[NH2:28][CH2:29][C@@H:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][C@H:31]1[O:41][CH2:42][CH3:43]>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]([NH:28][CH2:29][C@@H:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][C@H:31]2[O:41][CH2:42][CH3:43])=[O:21])[C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1
Reactant: CCOC(=O)N1CC[C@@H](CN)[C@H](OCC)C1
Reactant: O=C(O)c1cc(Cl)cc2c1OCCO2
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC[C@@H](CNC(=O)c2cc(Cl)cc3c2OCCO3)[C@H](OCC)C1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
At a temperature below 10° C., triethylamine (0.01 mol) was added to 7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid (0.01 mol) in chloroform (40 ml). Ethyl chloroformate 01 mol) was added at a temperature below 10IC and the mixture was stirred for 30 minutes at a temperature below 10° C. This mixture was added to a solution of intermediate (14) (0.01 mol) in chloroform (20 ml), at a temperature below 10° C. The reaction mixture was stirred for 30 minutes then washed with a 5% HCl solution, with water, dried, filtered and the solvent was evaporated, yielding 4 g of (trans)-ethyl 4-[[[(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)carbonyl]-amino]methyl]-3-ethoxy-1-piperidinecarboxylate (intermediate 15).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Br)=[CH:7][CH:8]=1)(=O)C.[Br:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.[CH2:21]([N:28]1CCC(=O)CC1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCOCC1.[S]>>[NH2:20][C:19]1[S:5][C:4]2[CH2:1][N:28]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:6][CH2:7][C:8]=2[C:18]=1[C:16]([C:14]1[S:15][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: N#CCC(=O)c1ccc(Br)s1
Reactant: CC(=O)c1ccc(Br)s1
Agent: [S]
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1ccc(Br)s1)CCN(Cc1ccccc1)C2
Yield: 72 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-bromothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-bromothiophene-2-carbonyl)acetonitrile (Steps A and B). 1-Benzyl-4-piperidone (van der Klein et al., (1999), J. Med. Chem. 42: 3629-3635), 2-(5-bromothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 72%; IR (KBr) cm−1: 3411, 2923, 1570, 1411, 1314, 978; 1H NMR (CDCl3):δ2.38 (t, J=5.4 Hz, 2H), 2.59 (t, 2H, J=5.4 Hz), 3.48 (s, 2H), 3.67 (s, 2H), 6.28 (bs, 2H), 7.01 (d, 1H, J=4 Hz), 7.15 (d, 1H, J=4 Hz), 7.32 (m, 5H); brown solid, mp: 87-89° C. (petroleum ether).
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[N:9]=[N+:10]([O-:15])[C:11]([Cl:14])=[CH:12][CH:13]=1.O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[OH:26]>O1CCOCC1.CS(C)=O>[Cl:14][C:11]1[N+:10]([O-:15])=[N:9][C:8]([O:26][C:20]2[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=2[O:18][CH3:17])=[CH:13][CH:12]=1
Reactant: [O-][n+]1nc(Cl)ccc1Cl
Reactant: COc1ccc(C)cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C)cc1Oc1ccc(Cl)[n+]([O-])n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
In a mixed solvent of 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) was dissolved 167.5 mg (1.21 mmol) of commercially available 2-methoxy-5-methylphenol, and 142.8 mg (1.27 mmol) of potassium tert-butoxide was added to the solution, then 202.9 mg (1.23 mmol) of 3,6-dichloropyridazine 1-oxide was added to the mixture and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=2:1) to obtain 226.5 mg (0.849 mmol, Yield: 70.2%) of 6-chloro-3-(2-methoxy-5-methylphenoxy)pyridazine 1-oxide.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[OH:9][C@H:10]([CH2:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C:12](OC)=[O:13].[Li]CC(OC(C)(C)C)=O.[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1>[OH:9][C@H:10]([CH2:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:11][C:12](=[O:13])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: COC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CC(=O)OC(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -70 °C
Yield: 126.2 %

Procedure:
Under a nitrogen atmosphere and at 0° C., 87.78 ml. of 1.5M. n-butyllithium/hexane (132 mmoles) is added dropwise to 18.49 ml. (132 mmoles) of diisopropylamine in 150 ml. of dry tetrahydrofuran, and the mixture is stirred for 30 minutes to form a solution of lithium diisopropylamide. The obtained solution is cooled to -70° C., a solution of 17.76 ml. (132 mmoles) of t-butyl acetate in 25 ml. of dry tetrahydrofuran is added over a period of 1 hour with stirring at -65°--70° C., the reaction mixture is stirred for 1.5 hours at the same temperature, a solution of 11.28 g. (30 mmoles) of methyl (S)-3-hydroxy-4-(triphenylmethoxy)butanoate (obtainable by Step 3 of Example 1) in 75 ml. of dry tetrahydrofuran is added to the obtained solution of t-butyl lithioacetate at -65°--70° C., and the yellow solution is stirred at about - 70° C. for 0.5 hour, warmed to -10° C. and stirred at -10° C. for 1 hour (with thin layer chromatography (TLC) monitoring to indicate when the reaction is over), the reaction mixture being stirred under nitrogen throughout. 150 ml. of saturated aqueous ammonium chloride is added to quench the reaction at -60°--70° C., the mixture is warmed to 0° C., transferred to a separatory funnel and diluted with ethyl acetate, and the organic phase is separated. The aqueous layer is extracted with an additional 200 ml. of ethyl acetate, and the organic phases are combined, washed successively with 90 ml. of 1N. hydrochloric acid and 90 ml. of saturated aqueous sodium bicarbonate, dried and filtered. The organic solution is evaporated to yield the crude product (17.43 g.) (estimated to be about 80% pure by chromatography analysis).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][O:12][C:5]2([CH2:11][CH2:10][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3]1.[CH2:15]([NH2:18])[CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:1][C:2]1([CH3:14])[CH2:13][O:12][C:5]2([CH2:11][CH2:10][C:8](=[N:18][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:6]2)[O:4][CH2:3]1
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Reactant: CCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN=C1CCC2(CC1)OCC(C)(C)CO2

Procedure:
A 500 ml round bottom flask was charged with 20.32 g (0.103 mol) of 3,3-dimethyl-1,5-dioxazpiro[5.5]undecan-9-one (also known as 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal, from Aldrich Chemical Company, Milwaukee, Wis.), 21.6 g (0.365 mol) of n-propylamine (Eastman Chemical Company, Rochester, N.Y.), 0.01 g of p-toluenesulfonic acid and 100 ml of toluene. The reaction mixture was refluxed for 24 hours with a water separator charged with 16 g of 3-A molecular sieves. The volatiles were removed in vacuo and the residue was held for further synthetic modifications as described below.
Reaction SMILES: OCCCC[C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cr](Cl)([O-])(=O)=[O:14].[NH+]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:14]
Reactant: OCCCCC1(O)CCCCC1
Reactant: c1cc[nH+]cc1
Reactant: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: O=CCCCCC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 8 (10 gm, 6.33 mmol) in methylene chloride (25 ml) was added pyridinium chlorochromate (1.64 gm, 7.6 mmol) and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was passed through a silica column and eluted by methylene chloride to afford a pure hydroxy-aldehyde, 9 (0.7 gms).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[N:14][N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.C(Cl)Cl.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2nc(N3CCCC3)c3cc(-c4cccnc4)ncc32)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(-c2cc3c(N4CCCC4)n[nH]c3cn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
To a solution of 5-(pyridin-3-yl)-3-(pyrrolidin-1-yl)-1-trityl-1H-pyrazolo[3,4-c]pyridine (0.120 g, 0.236 mmol) in Methylene chloride (3.030 mL, 47.28 mmol) was added Triethylsilane (0.151 mL, 0.946 mmol) and Trifluoroacetic Acid (3.642 mL, 47.28 mmol). The mixture was stirred at RT for 3 h. The reaction was concentrated. The crude was submitted for HPLC purification in DMF to give 252 (22.4 mg, 35.7% yield). ESI MS m/z=266.1 (M+1). 1H NMR (400 MHz, DMSO) δ 12.34 (s, 1H), 9.30 (d, J=1.8 Hz, 1H), 8.90 (d, J=0.9 Hz, 1H), 8.53 (dd, J=4.7, 1.5 Hz, 1H), 8.50-8.42 (m, 1H), 8.32 (s, 1H), 7.47 (dd, J=7.9, 4.7 Hz, 1H), 3.63 (t, J=6.5 Hz, 4H), 1.99 (t, J=6.5 Hz, 4H)
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:18])[C@H:5]([C@H:14]([CH2:16][CH3:17])[CH3:15])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[I-:19].[Na+]>C(#N)C>[I:19][CH2:2][O:3][C:4](=[O:18])[C@H:5]([C@H:14]([CH2:16][CH3:17])[CH3:15])[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: [I-]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCI
Temperature: 60 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of N-BOC-L-isoleucine chloromethyl ester (19.6 g, 70 mmol) in acetonitrile (300 mL), was added sodium iodide (31.5 g, 210 mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2 and washed with aqueous sodium thiosulmte (0.1 M). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 2% MeOH in CH2Cl2), to give 22.6 g of N-BOC-L-isoleucine iodomethyl ester.
Reaction SMILES: [C-]#N.[Na+].[Cu][C:5]#[N:6].Br[C:8]1[C:9]([NH2:25])=[N:10][C:11]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:13]=1>CN(C)C=O>[NH2:25][C:9]1[C:8]([C:5]#[N:6])=[N:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:11]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:10]=1
Reactant: N#C[Cu]
Reactant: Nc1nc(-c2ccco2)c(-c2ccncc2)nc1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(-c2ccncc2)c(-c2ccco2)nc1N
Temperature: 120 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of sodium cyanide (21 mg, 0.42 mmol) and copper (I) cyanide (38 mg, 0.42 mmol) in anhydrous dimethylformamide (1.5 mL) was heated to 120° C. 3-Bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 62, 90 mg, 0.28 mmol) was added in portions. After stirring at 120° C. for two hours, the mixture was cooled and evaporated. A 0.75M aqueous solution of sodium cyanide (6 mL) was added, stirred for 10 min at room temperature and partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4), and evaporated. Silica gel flash column chromatography (dichloromethane/methanol 98:2) furnished the title compound as a dark yellow solid (52 mg, 70%).