Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:25][O:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][N:17]3[C:21]([CH3:23])([CH3:22])[O:20][N:19]=[C:18]3[CH3:24])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:29]>CO>[CH2:27]([O:26][CH2:25][C:13]1[N:14]([CH2:15][CH2:16][N:17]2[C:21]([CH3:23])([CH3:22])[O:20][N:19]=[C:18]2[CH3:24])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:29])[C:11]=2[N:12]=1)[CH3:28]
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCN1C(C)=NOC1(C)C
Reactant: N
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCN1C(C)=NOC1(C)C
Temperature: 150 °C
Reaction time: 15 h

Procedure:
A slurry of 4-chloro-2-ethoxymethyl-1-[2-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)ethyl]-1H-imidazo[4,5-c]quinoline (670 mg, 1.67 mmol) in a solution of 7 M ammonia in methanol (20 mL) was sealed in a pressure vessel and heated to 150° C. After 15 hours, the volatiles were removed under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution from 97:3 to 95:5 dichloromethane/methanol) to afford 2-ethoxymethyl-1-[2-(3,5,5-trimethyl-1,2,4-oxadiazol-4(5H)-yl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (350 mg) as a white solid that was recrystallized from acetonitrile to give white needles, mp 204-205° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12.[CH3:12][O:13][C:14](=[O:30])[C:15](=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH3:12][O:13][C:14](=[O:30])[CH:15]([CH:23]([N:9]1[C:5]2=[N:6][CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]2[CH:11]=[CH:10]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17]
Reactant: COc1ccnc2[nH]ccc12
Reactant: COC(=O)C(=Cc1ccccc1)C(=O)OC(C)(C)C
Product: COC(=O)C(C(=O)OC(C)(C)C)C(c1ccccc1)n1ccc2c(OC)ccnc21

Procedure:
2-[(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-phenyl-methyl]-malonic acid tert-butyl ester methyl ester was prepared from 4-methoxy-1H-pyrrolo[2,3-b]pyridine (WO03/082289) and 2-benzylidene-malonic acid tert-butyl ester methyl ester using the procedure of Example 7, and was used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][C:19]#[N:20])=[N:16][CH:17]=3)[C:6]=2[CH:21]=1>[Ni]>[Cl:1][C:2]1[C:3]([C:22]([F:23])([F:24])[F:25])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[N:16][CH:17]=3)[C:6]=2[CH:21]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CC#N)nc1
Agent: [Ni]
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCN)nc1

Procedure:
To a solution of {5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}acetonitrile added Raney-Ni and stirred for 8 h under hydrogen atmosphere (3.0 kgf/cm2). The catalyst was filtered off and the solvent was removed. The residue was diluted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated to give 813 mg of title compound as black solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1([CH3:12])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>CCCCCC>[C:1]([NH:5][S:6]([C:9]1([CH2:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)C1(C)CC1
Reactant: BrCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)C1(Cc2ccccc2)CC1
Yield: 60 %

Procedure:
This compound was obtained in 60% yield using the procedure described for the synthesis of N-tert-butyl-(1-methyl)cyclopropylsulfonamide except 1.05 equivalents of benzyl bromide were used, followed by trituration with 10% ethyl acetate in hexane: 1H NMR (CDCl3) δ 0.92 (m, 2H), 1.36 (m, 2H), 1.43 (s, 9H), 3.25 (s, 2H), 4.62 (br s, 1H), 7.29-7.36 (m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.Br[CH2:29][CH:30]([CH3:32])[CH3:31]>>[CH2:29]([O:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:25][CH3:26])[C:4]([OH:3])=[O:27])=[CH:12][CH:11]=2)=[CH:23][CH:22]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CBr
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(O)cc2)cc1)OC
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OCC(C)C)cc2)cc1)C(=O)O

Procedure:
(2S)-3-{4-[3-(4-Hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 263, Step B) was coupled under the ester J with 1-bromo-2-methylpropane to afford the title compound. 1H-NMR (CDCl3, 200.15 MHz): δ 7.14 (d, 2H, J=8.6), 6.86–6.82 (m, 6H), 4.11 (q, 4H, J=6.2), 3.98 (dd, 1H, J=7.3, 4.6), 3.66 (d, 2H, J=6.5), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.5, 4.6), 2.95 (dd, 1H, J=14.5, 7.3), 2.21 (qn, 2H, J=6.2), 2.11–1.98 (m, 1H), 1.01 (d, 6H, J=6.7).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=[CH2:24])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.O=C1CCC(=O)N1[O:39][C:40](=O)[CH:41]=[N+:42]=[N-:43]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10](=[CH2:24])[CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH3:23])[C:40](=[O:39])[CH:41]=[N+:42]=[N-:43])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C=C(CNCc1ccc(OC)cc1OC)CO[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=CC(=O)ON1C(=O)CCC1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(CO[Si](C)(C)C(C)(C)C)CN(Cc1ccc(OC)cc1OC)C(=O)C=[N+]=[N-]
Reaction time: 16 h
Yield: 48.7 %

Procedure:
To a solution of [2-(tert-butyldimethylsilanyloxymethyl)allyl]-(2,4-dimethoxybenzyl)amine (384 mg) in chloroform (3.8 ml) were sequentially added triethylamine (0.23 ml) and diazoacetic acid 2,5-dioxopyrrolidin-1-yl ester (200 mg) at room temperature, and the mixture was stirred for 16 hours. This reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to give the titled compound (223 mg).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([NH:10][C@H:1]2[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]2)[CH:20]=[CH:19]3)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=413.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 1-fluoro-4-isocyanato-benzene.
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[CH2:4].[C:10](=[O:12])=[O:11]>C1COCC1>[CH:3]([C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[C:10]([OH:12])=[O:11])=[CH2:4]
Reactant: O=C=O
Reactant: C=CC1(Br)C=CC=CC1
Solvent: C1CCOC1
Product: C=CC1(C(=O)O)C=CC=CC1
Temperature: 25 °C
Yield: 66 %

Procedure:
Compound CC was prepared in the following manner. Mg turnings (1.75 g, 0.072 g atom) were placed in an oven dried 250 ml 3 neck flask with condenser and addition funnel (all assembled hot). The entire apparatus was evacuated and filled with argon. The flask was charged with 10 ml of anhydrous THF and the addition funnel was charged with 8.0 gm (43.7 mmol) of 1-bromostyrene in 50 ml of anhydrous THF. Five (5) ml of the 1-bromostyrene solution was added to the Mg turnings and the mixture was heated to 65°-70° C. and the remainder of the solution was added over 1 hour. The mixture was heated an additional 30 min., then cooled to room temperature over 1 hour, then poured over crushed dry ice and the dry ice was allowed to evaporate. The mixture was made strongly acidic with 150 ml of 10% HCl solution. The organic phase was separated and the aqueous phase was extracted three times with ether. The combined organic phase was poured into 150 ml of 20% KOH solution, the solution was separated and the basic phase was filtered to remove polymer. The basic phase was then acidified with 10% HCl solution and extracted three times with 100 ml portions of ether. The extracts were combined, washed with 100 ml of brine and dried over Na2SO4. The solution was filtered and concentrated to a white solid which was recrystallized from chloroform/hexane solution to yield 6.44 g (66%) of 1-vinylbenzoic acid in two crops.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[Na].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[I-].[Na+]>CC(C)=O>[CH2:20]([O:19][C:13](=[O:18])[CH:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4])[C:15](=[O:16])[CH3:17])[CH3:21]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Yield: 98.4 %

Procedure:
A mixture of 2-chloro-1-(4-fluoro-phenyl)-ethanone (4.83 g, 28.0 mmol), ethyl acetoacetate sodium salt (4.26 g, 28.0 mmol) and sodium iodide (420 mg, 2.80 mmol) in acetone (50 mL) was refluxed for 1 h; then the solvents were evaporated, the residue was partitioned between EtOAc and 1 M HCl aqueous solution, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, to give a brown liquid, the title product (7.334 g); 1H NMR (200 MHz, CDCl3): δ (ppm)=8.1-7.9 (m, 2H), 7.2-7.1 (m, 2H), 4.22 (q, 2H, J=6.8 Hz), 4.2-4.0 (m, 1H), 3.8-3.4 (m, 2H), 2.44 (s, 3H), 1.30 (t, 3H, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([C:32]([F:35])([F:34])[F:33])=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[ClH:36]>C(Cl)Cl.CCOCC>[ClH:36].[F:1][C:2]1[C:3]([C:32]([F:35])([F:33])[F:34])=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cccc(F)c4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cccc(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a solution of tert-butyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (29, 0.066 g, 0.13 mmol) in CH2Cl2 (2 mL) was added HCl (2 mL, 2.0 N solution in Et2O). The mixture stirred at ambient temperature for 18 h, was diluted with Et2O (30 mL), and the resulting solids were collected by filtration to give (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (30) as a white solid (0.027 g, 47%): 1H NMR (300 MHz, DMSO-d6) δ 9.46-9.20 (m, 2H), 7.74-7.61 (m, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.37-7.25 (m, 1H), 4.70-4.44 (m, 2H), 4.34-4.22 (m, 2H), 3.50-3.10 (m, 4H), 2.93-2.76 (m, 3H), 1.86-1.60 (m, 4H); ESI MS m/z 468 [M+H]+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][CH2:11][NH2:12])[CH:9]=1)([O-:4])=[O:3].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].O>O1CCCC1>[N+:2]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][CH2:11][NH:12][C:20](=[O:22])[CH3:21])[CH:9]=1)([O-:4])=[O:3]
Reactant: CC(=O)Cl
Reactant: NCCn1cc([N+](=O)[O-])cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanamine hydrochloride (1.0 g) obtained in Step B of Example 348 in tetrahydrofuran (30 mL) were successively added triethylamine (2.2 mL) and acetyl chloride (0.44 mL) in an ice bath, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized (hexane/ethyl acetate) to give the title compound (610 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH2:18]([O:20][C:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22])[CH3:19].C(OCC)(=O)C.[F-].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:21]([O:20][C:18]([C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1)=[CH2:19])[CH3:22]
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(OCC)c1cc(OC)c(Oc2ccccc2C)nn1
Reaction time: 8 h
Yield: 14.1 %

Procedure:
In toluene (6.5 mL) was dissolved 321 mg (1.28 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 534 mg (1.48 mmol) of (1-ethoxyvinyl)(tributyl)tin, then 155.3 mg (0.134 mmol) of tetrakis(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours and 20 minutes. The reaction mixture was allowed to stand at room temperature overnight, then, ethyl acetate, water and sodium fluoride were added to the mixture and the resulting mixture was stirred for 2 hours. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, and the organic layer was separated, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 51.8 mg (0.181 mmol, Yield: 14.1%) of 6-(1-ethoxyvinyl)-4-methoxy-3-(2-methylphenoxy)pyridazine.
Reaction SMILES: [C:1]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])#[C:2][CH2:3][CH2:4][CH3:5]>[Cu](I)I.CN(C)C=O>[CH2:3]([C:2]1[NH:8][C:7]2[C:6]([CH:1]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH3:5]
Reactant: CCCC#Cc1ccccc1N
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: CCCc1cc2ccccc2[nH]1
Temperature: 140 °C
Yield: 80 %

Procedure:
A mixture of 2-pent-1-ynylaniline (0.25 g, 1.57 mmol), copper iodide (30 mg, 0.16 mmol), and N,N-dimethylformamide (6 mL) was heated at 140° C. for 4 hours and concentrated. The crude material was dissolved in diethyl ether, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure. The residue was purified by automated flash chromatography eluting with a gradient of 0-20% ethyl acetate in hexanes to provide 0.20 g of 2-propyl-1H-indole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(O)cc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF (116 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 204° C.; 1H NMR (250 MHz, DMSO-d6) δ3.96 (s, 2 H), 6.55 (s, 1 H), 6.88 (d, 2 H), 7.39 (m, 5 H), 7.63 (d, 2 H), 10.28 (s, 1 H), 11.75 (bs, 1 H).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[NH:15][C:14](=[O:16])[C:13]3[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O[C@H:24]([C@H:26]1[CH2:30][N:29]([C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH3:32])[C:28](=[O:41])[CH2:27]1)[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(Cl)Cl>[C:1]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([O:16][C@@H:24]([C@H:26]3[CH2:30][N:29]([C@@H:31]([C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)[CH3:32])[C:28](=[O:41])[CH2:27]3)[CH3:25])[C:13]3[N:17]([CH:20]([F:21])[F:22])[CH:18]=[N:19][C:12]=3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1cc(-c2cc3ncn(C(F)F)c3c(=O)[nH]2)cn1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4cnn(C(C)(C)C)c4)cc4ncn(C(F)F)c34)CC2=O)cc1
Temperature: 40 °C
Reaction time: 1.25 h

Procedure:
6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one 2.33 (33 mg, 0.107 mmol), lactam alcohol 1.05 (42 mg, 0.16 mmol), and PPh3 (44 mg, 0.17 mmol) were taken up in THF (1 mL). To the resulting suspension was added DEAD (26 μL, 0.17 mmol) dropwise. The resulting cloudy solution was heated to 40° C. and stirred 1.25 h. The solution was then diluted with DCM and concentrated directly onto silica gel. Purification by silica gel chromatography (15% to 60% acetone in hexanes) afforded (R)-4-((R)-1-(6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.34 that was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][C:14]=3[C:23]([F:26])([F:25])[F:24])=O)(C)(C)C.[ClH:30]>CCOCC.O>[ClH:30].[CH3:21][CH:20]([CH3:22])[CH2:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:27])[N:11]3[CH2:28][CH2:29][NH:8][CH2:9][C@H:10]32)=[C:14]([C:23]([F:25])([F:24])[F:26])[CH:15]=1
Reactant: CC(C)Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methylpropyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (25 mg, 0.06 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 16 mg of a white solid. MS (ESI) 313 (M−Cl).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(F)c(F)n1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)nc1F
Temperature: 60 °C
Yield: 56.7 %

Procedure:
To a 3-neck, round-bottomed flask was added 2,3,6-trifluoropyridine (25 g, 0.19 mol) followed by the addition of red fuming nitric acid (210 mL, 4.7 mol). Sulfuric acid (150 mL, 2.8 mol) was added to this mixture slowly via an addition funnel, maintaining internal temperature below 40° C. The resulting solution was heated to 60° C. for 30 minutes and allowed to cool to room temperature after heating. This solution was then further cooled in an ice-water bath and inversely quenched into a 2-L Erlenmeyer flask containing a mixture of ice and water (700 mL, 1:1 ratio). The quenched solution was then transferred to a 2-L separatory funnel and partitioned with hexanes (600 mL). The aqueous layer was subsequently washed with hexanes (600 mL) and methylene chloride (600 mL). The combined organic layers were then dried over Na2SO4, filtered, and concentrated to provide the title compound as a light yellow liquid (19.2 g, 57% yield).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:6]=1)#[CH:4].Cl>CN(C=O)C.CO>[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:6]=1)#[CH:4]
Reactant: C#Cc1nn(C2CCCCO2)c2ccc(C(=O)OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1nn(C2CCCCO2)c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
Sodium hydroxide (100 mL; 5.0 M; 500 mmol; 18.1 eq.) was added in one portion to a solution of methyl 3-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (7.9 g; 27.7 mmol; 1.0 eq.) in DMF (100 mL) and MeOH (100 mL). The reaction mixture was stirred at RT for 1 h, then poured into a 1N HCl solution (pH 1) and extracted with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The brown solid obtained was triturated with MeOH to give the title compound as a red solid (4.83 g, 65%). 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.35-8.28 (m, 1H), 8.04 (dd, J=8.9, 1.5 Hz, 1H), 7.90 (dd, J=8.9, 0.6 Hz, 1H), 5.95 (dd, J=9.5, 2.3 Hz, 1H), 4.73 (s, 1H), 3.94-3.84 (m, 1H), 3.83-3.69 (m, 1H), 2.43-2.27 (m, 1H), 2.09-1.93 (m, 2H), 1.83-1.65 (m, 1H), 1.64-1.52 (m, 2H). HPLC (max plot) 99.5%; Rt %3.17 min. UPLC/MS: (MS−) 269.3.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[CH3:19])O)=[CH:7][CH:6]=1)C.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)c1ccc(C(O)c2cnccc2C)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccncc1Cc1ccc(C=O)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A mixture of 400 mg of the hydroxymethyl compound (prepared as described in Reference Example 4), 5 ml of benzene and 196 μof thionyl chloride was stirred at 40° C. for one hour, and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and the mixture extracted with chloroform. The extract was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. To the residue were added 5 ml of acetic acid and 175 mg of zinc powder, and the mixture stirred at room temperature for one hour, and then concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and concentrated under reduced pressure to give 166 mg of the title compound having the following physical characteristics:
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:3][C:4]#[N:5].[OH:12][CH2:13][CH2:14][NH:15][NH2:16]>CCO>[NH2:5][C:4]1[N:15]([CH2:14][CH2:13][OH:12])[N:16]=[C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:3]=1
Reactant: NNCCO
Reactant: N#CCC(=O)c1ccccn1
Solvent: CCO
Product: Nc1cc(-c2ccccn2)nn1CCO
Yield: 80.6 %

Procedure:
A solution of 3-oxo-3-pyridin-2-yl-propionitrile (0.5 g, 3.4 mmol; CAS 54123-21-6) in EtOH (20 ml) was treated with 2-hydroxyethylhydrazine (0.7 ml, 10.3 mmol). The reaction mixture was refluxed overnight, then concentrated. After silica gel chromatography using a CH2Cl2/MeOH gradient, the product was obtained as viscous yellow oil (0.56 g, 80%).