Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: COc1ccc(Sc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1

Procedure:
The title compound was prepared from 4-methoxybenzenethiol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 239.4–242.3° C. 1H NMR (acetone-d6/300 MHz) 7.84 (s, 1H), 7.55 (m, 3H), 7.16 (d, 2H, J=8.7 Hz), 6.20 (s, 1H), 5.75 (q, 1H, J=7.0 Hz), 3.90 (s, 3H). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz). ESLRMS m/z 415 (M−H). ESHRMS m/z 415.0005 (M−H, Calc'd 415.0019). Anal. Calc'd for C18H12ClF3O4S: C, 51.87; H, 2.90; Cl, 8.51; S, 7.69. Found: C, 51.76; H, 2.83; Cl 8.55; S, 7.77.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH:9]=O)C>C(O)(=O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:7]2[O:6][C:5]([CH:4]=[O:3])=[CH:9][C:8]=2[CH:11]=1
Reactant: CCOC(COc1ccc(OC)cc1C=O)OCC
Solvent: CC(=O)O
Product: COc1ccc2oc(C=O)cc2c1
Yield: 24.3 %

Procedure:
A stirred solution of 23 (1.0 g, 3.74 mmol) in acetic acid (10 mL) was refluxed for 16 h. After cooling, the solution was evaporated to dryness. The crude product was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 24 (160 mg, 24%) as a white solid. 1H NMR (500 MHz, CDCl3): δ: 9.80 (1H, s, CHO), 7.49-7.45 (2H, m, ArH), 7.12-7.09 (2H, m, ArH), 3.85 (3H, s, OCH3).
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].[N-:26]=[N+:27]=[N-:28].[Na+]>>[C:18]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]4[NH:28][N:27]=[N:26][N:17]=4)=[CH:15][C:9]=3[O:8]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: c1ccc(C2(c3ccccc3)Oc3ccc(-c4nnn[nH]4)cc3O2)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
2,2-Diphenyl-1,3-benzodioxol-5-carbonitrile (4.79 g) are heated at 160° C. for 5 hours with 1.71 g of ammonium chloride and 2.08 g of sodium azide. The reaction mixture is cooled to room temperature and partitioned at pH 3 between water and ethyl acetate. The organic phase is shaken with water and the pH value is adjusted to 10 with 1N aqueous sodium hydroxide solution. The aqueous phase (pH 10) is separated, shaken with ethyl acetate and the pH value is adjusted to 4. A white precipitate forms. This is filtered off, dried and recrystallized from 240 ml of acetonitrile. There are obtained 3.84 g of 5-(2,2-diphenyl-1,3-benzodioxol-5-yl)-1H-tetrazole as white crystals of melting point 212°-215° C./dec.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:30][C:31]1[CH:32]=[C:33]([S:37]([NH:40][CH:41]2[CH2:43][CH2:42]2)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[CH:41]1([NH:40][S:37]([C:33]2[CH:32]=[C:31]([NH:30][C:27]([C:26]3[CH:25]=[N:24][N:17]4[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]([C:6]5[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=5)=[N:15][C:16]=34)=[O:28])[CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH2:43][CH2:42]1
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC5CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.11) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 612.2 [(M−H)−]; mp 225° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CN1CCCc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C

Procedure:
To a solution of 7-amino-1-methyl-1,2,3,4-tetrahydroquinoline (D3) (325 mg, 2 mmol) in DCM (10 ml) was added 4-biphenylcarboxylic acid (476 mg, 2.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (444 mg, 2.4 mmol) and the reaction stirred at ambient temperature. After 1 h the reaction mixture was filtered to give the title compound as a white solid. The filtrate was diluted with DCM, washed with sat. aq. sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo to give further crude product which was purified by silica SPE chromatography. Elution with an EtOAc/60-80° C. petroleum ether gradient gave a mixture of the title compound and the starting acid. These fractions were washed with further sat. aq. sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo to give further title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.94 (d, 2H), 7.70 (m, 3H), 7.63 (d, 2H), 7.48 (t, 2H), 7.40 (t, 1H), 7.07 (d, 1H), 6.93 (d, 1H), 6.75 (dd, 1H), 3.25 (m, 2H), 2.94 (s, 3H), 2.76 (t, 2H), 1.98 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.C([Li])CCC.Cl[Si](C)(C)C.[CH3:17][CH2:18][C:19](=[O:22])[CH2:20][CH3:21]>C1COCC1>[NH2:1][C:2]1[S:3][C:4]([C:19]([OH:22])([CH2:20][CH3:21])[CH2:18][CH3:17])=[N:5][N:6]=1
Reactant: Nc1nncs1
Reactant: CCC(=O)CC
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)(CC)c1nnc(N)s1
Temperature: -20 °C

Procedure:
To a −78° C. solution of 2-amino-1,3,4-thiadiazole (commercially available) (2.5 g, 24.72 mmol) in THF (200 mL, 0.1M) was added first n-butyllithium 1.6M hexanes (30.9 mL, 49.4 mmol) followed 15 min later by chlorotrimethylsilane (6.27 mL, 49.4 mmol). The temperature raised to −20° C. for 15 min and cooled back to −78° C. More n-butyllithium 1.6M hexanes (15.45 mL, 24.72 mmol) was added followed 15 min later by 3-pentanone (2.62 mL, 24.72 mmol). The solution was then warmed to rt (overnight). The reaction mixture was quenched with a saturated NH4Cl solution and THF was removed under vacuum. The aqueous phase was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over MgSO4 and concentrated. The crude residue obtained was purified by column chromatography (100% EtOAc) to yield the title compound. 1H NMR (400 MHz, acetone-d6): δ 6.3 (bs, 2H), 4.4 (bs, 1H), 2.0-1.7 (m, 4H), 0.9 (t, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1.I[CH2:21][CH3:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][CH2:21][CH3:22])=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1
Reactant: Oc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1
Reactant: CCI
Product: CCOc1ccc2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
The above 5-bromo-2-chloro-1-(5-hydroxybenzo[b]thiophen-2-ylmethyl)benzene and iodoethane were treated in a manner similar to Reference Example 132-(2) to give the desired 5-Bromo-2-chloro-1-(5-ethoxybenzo[b]thiophene-2-ylmethyl)-benzene. APCI-Mass m/Z 382/380 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NCC(F)(F)F)n(C)n1
Yield: 64 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (30 mg, 64%) which was obtained as a white solid. MS: m/e=409.0 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:26]=[C:25]([CH:32]=O)[CH:24]=2)=[CH:19][CH:18]=1>>[C:28]([N:27]1[C:23]([C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=2)=[CH:24][C:25]([CH2:32][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[N:26]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: CC(C)(C)n1nc(CNCCN2CCN(c3ccccc3)CC2)cc1-c1ccc(Cl)cc1
Yield: 69.1 %

Procedure:
Compound 11 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]=[CH:3]1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][C:3]1[C:2](=[O:1])[NH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]=1
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Temperature: 80 °C
Yield: 74.9 %

Procedure:
To a solution of ethyl 6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylate (Organic Process Research and Development 1997, 1, 370-378; 0.10 g) in carbon tetrachloride was added N-bromosuccinimide (0.083 g). The mixture was heated at 80° C. for 24 h. Evaporation and the purification by flash column chromatography gave the subtitle compound as a colourless solid (0.10 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]C)=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2ccc(CC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.89 g), methyl 2-(4-hydroxyphenyl)acetate (0.50 g), anhydrous potassium carbonate (0.49 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained crystal, tetrahydrofuran (6 mL) and methanol (6 mL) was added a 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 2 hrs. Dilute hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.13 g, 93%) of 2-[4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 179-180° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[CH:16][CH:17]=1.[BH4-].[Na+].CO>C(O)(=O)C>[CH3:29][N:18]([CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)[C:15]1[N:14]=[N:13][C:12]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[OH:1])[CH:8]([OH:11])[CH2:7][CH2:6]3)=[CH:17][CH:16]=1
Reactant: CN(c1ccc(-c2cc3c(cc2O)C(=O)CC3)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(c1ccc(-c2cc3c(cc2O)C(O)CC3)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a microwave vial was added 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one (Example 35-1, 50 mg, 0.13 mmol), sodium borohydride (9.59 mg, 0.25 mmol) and MeOH (1.5 mL). The resulting suspension was stirred at RT for two hours. The reaction mixture was acidified with excess acetic acid and loaded onto an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford the title compound. MS [M+H+]=397.3, LCMS Rt=0.46 min [LCMS Method Q]; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.11 (d, J=9.54 Hz, 1H), 7.64 (s, 1H), 7.31 (d, J=9.54 Hz, 1H), 6.99 (s, 1H), 5.16 (t, J=6.53 Hz, 1H), 5.01-5.13 (m, 1H), 2.95-3.08 (m, 4H), 2.73-2.86 (m, 1H), 2.41-2.54 (m, 1H), 1.91 (s, 1H), 1.53-1.78 (m, 4H), 1.41 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: [C:1]([NH:4][N:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([NH:8][CH3:9])=[O:7])(=[O:3])[CH3:2].CI.[C:18](=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([N:4]([CH3:18])[N:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([NH:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)N(NC(C)=O)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: CNC(=O)N(c1ccccc1)N(C)C(C)=O
Yield: 55.1 %

Procedure:
A mixture of 17 g (0.082 mol) of the semicarbazide prepared above, 14.2 g (0.1 mol) methyl iodide, 14.0 g (0.1 mol) potassium carbonate, and 200 ml ethanol was refluxed for 2 hours, cooled, filtered and evaporated under reduced pressure. The resulting residue was diluted with dichloromethane, filtered to remove suspended solids, washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to give 10 g of crude 1-acetyl-1,4-dimethyl-2-phenyl-semicarbazide.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][C:28](=O)[CH2:29]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:32]([F:34])=[CH:33][C:24]=3[F:23])[CH2:29]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1CCc2c(F)cc(F)cc2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1CCc2c(F)cc(F)cc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 5,7-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 20.6, 24.3, 26.6, 28.4, 29.3, 36.5, 36.6, 37.1, 52.6, 56.0, 59.1, 60.6, 67.2, 101.3, 104.7, 111.2, 131.1, 172.3; MS m/z 474.4 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.N>O>[N:20]1[CH:21]=[CH:22][C:17]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[CH:18][CH:19]=1
Reactant: Clc1ccncc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 31 %

Procedure:
4-(piperazin-1-yl)anisole (4.24 g) and 4-chloropyridine hydrochloride (3.35 g) were intimately mixed and heated at 160°-170° C. (bath temperature) for 7 minutes. The solid obtained on cooling was dissolved in water (75 ml) and the solution basified with aqueous ammonia. The solid precipitate was extracted into ethyl acetate and the organic extract washed with water, filtered through phase separating paper (Whatman 1PS) and evaporated. The residue was recrystallised from ethanol to give 4-[4-(4-pyridyl)piperazin-1-yl]anisole (1.84 g) as a solid: m.p. 165°-167° C.; NMR (CDCl3) δ8.3(2H,d); 6.86(4H,m); 6.71(2H,d); 3.78(3H,s); 3.46(4H,m); 3.2(4H,m).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:22]=[CH:21][C:12]2[S:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:11]=2[C:10]=1[N+:23]([O-])=O)([C:3](OCC)=[O:4])=[O:2]>C(O)C.[Pd]>[CH2:19]([O:18][C:16]([C:14]1[S:13][C:12]2[CH:21]=[CH:22][C:9]3[N:8]=[C:1]([OH:2])[C:3]([OH:4])=[N:23][C:10]=3[C:11]=2[CH:15]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(=O)Nc1ccc2sc(C(=O)OCC)cc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2c(ccc3nc(O)c(O)nc32)s1
Yield: 62.9 %

Procedure:
A solution of 5-ethoxalylamino-2-ethoxycarbonyl-4-nitrobenzo-[b]thiophene (0.B4 g, 2.3 mmol) in ethanol was hydrogenated at atmospheric pressure and room temperature in the presence of 0.55 g of 5% palladium-on-charcoal. The catalyst was removed by filtration and washed with ethanol. The filtrate was heated to reflux for 11/2 h, and cooled. The resulting precipitate was collected by filtration and washed with ethanol to give 0.42 g (63%) of the title compound, m.p. 357°-361° C.; IR (KBr): 1680 cm--1 ; 1H-NMR (DMSO-d6): 1.36 (t, J=7 Hz, 3H, CH3), 4.37 (q, J=7 Hz, 2H, CH2), 7.33 (d, J=9 Hz, lH, ArH), 7.73 (d, J=9 Hz, lH, ArH), 8.83 (s, lH, H-9), 12.06 and 12.30 (2 broad s, 2H, 2 OH).
Reaction SMILES: BrC1C=[C:4]2[CH:10]=[N:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=NC=1.[Br:18][C:19]1[CH:20]=C2NN=CC2=[N:23][CH:24]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CCN(CC)CC>CN(C)C1C=CN=CC=1.C(#N)C>[Br:18][C:19]1[CH:20]=[C:5]2[N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[N:9]=[CH:10][C:4]2=[N:23][CH:24]=1
Reactant: Brc1cnc2cn[nH]c2c1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Br)cnc21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1ncc2ncc(Br)cc21
Yield: 93 %

Procedure:
Analogous to the preparation of tert-butyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate, 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.0 g, 10.10 mmol) was reacted with di-tert-butyl dicarbonate (2.8 g, 13.10 mmol), NEt3 (1.44 g, 2.0 mL, 14 mmol) and 4-(dimethylamino)pyridine in acetonitrile (20 mL) for 3 h. Work-up as discussed previously in the preparation of tert-butyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate provided desired product of tert-butyl 6-bromo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate as a brown solid (2.8 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C-:14]#[N:15].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:14]#[N:15])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
A mixture of 4-methyl-3-trifluorobromobenzene (33.26 g, 104.261 mmol) from step 1 above KCN (20.43 g, 313.67 mmol) and tetrabutylammonium bromide (3.37 g, 10.45 mmol) in CH2Cl2/H2O 1:1 (300 mL) was stirred at room temperature for 4 hours. The layers were separated and the organic layer washed with H2O (100 mL) 1N HCl (100 mL), brine, dried over Na2SO4 and then concentrated to a brown oil which was purified by flash column chromatography (0% to 20% EtOAc in hexanes) to give the product as a clear oil (14.9 g, 54%). 1H NMR (400 MHz, CDCl3) δ 3.91 (s, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.75 (dd, J=8.3, 2 Hz, 1H), 7.84 (d, J=2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]([NH:16][C:17](=[S:32])[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:10]1=[O:33].I[CH3:35]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]([N:16]=[C:17]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH2:20]2)[S:32][CH3:35])[C:10]1=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=S)NN2CC(O)CC(c3ccc(F)cc3Cl)C2=O)CC1
Reactant: CI
Solvent: CN(C)C=O
Product: CSC(=NN1CC(O)CC(c2ccc(F)cc2Cl)C1=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C

Procedure:
To a solution of tert-butyl 4-(3-((3SR,5SR)-3-(2-chloro-4-fluorophenyl)-5-hydroxy-2-oxopiperidin-1-yl)thioureido)piperidine-1-carboxylate (1.2 g, 2.4 mmol) in DMF (5 mL) was added iodomethane (0.2 mL, 3.6 mmol) and the reaction heated to 90° C. for 15 minutes. The reaction was evaporated to dryness, redissolved in ethyl acetate, washed with saturated sodium hydrogen carbonate, water, brine, dried with sodium sulfate and the solvent was evaporated in vacuo. The title compound, a mixture of geometrical isomers, was used crude in the next step (1.2 g, 99%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([N:9]2[CH2:18][CH2:17][C:16]3[N:15]=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][C:11]=3[CH2:10]2)=[O:8])[C@H:4]([CH:23]([CH3:25])[CH3:24])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:23]([C@H:4]1[N:5]([C:7]([N:9]2[CH2:18][CH2:17][C:16]3[N:15]=[CH:14][C:13]([C:19]([F:21])([F:20])[F:22])=[CH:12][C:11]=3[CH2:10]2)=[O:8])[CH2:6][C:2](=[O:1])[CH2:3]1)([CH3:25])[CH3:24]
Reactant: CC(C)[C@@H]1C[C@@H](O)CN1C(=O)N1CCc2ncc(C(F)(F)F)cc2C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@@H]1CC(=O)CN1C(=O)N1CCc2ncc(C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of ((2S,4R)-4-hydroxy-2-isopropyl-pyrrolidin-1-yl)-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone (prepared as in example #1) (0.118 g, 0.330 mmol) in DCM (4 mL) was added Dess-Martin periodinane (0.210 g, 0.495 mmol). The reaction mixture was stirred at ambient temperature for about 40 min. Additional Dess-Martin reagent (0.303 g, 0.714 mmol) was added in portions over about 4 h and the reaction mixture was stirred for about 16 h. Saturated aqueous sodium bicarbonate (4 mL) was added and the organic portion was separated, dried over MgSO4, filtered, and concentrated to afford (S)-5-isopropyl-1-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridine-6-carbonyl)-pyrrolidin-3-one as a sticky yellow solid that was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method d) Rt 2.49 min; m/z: (M+H)+ 356.