Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.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>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]=[C:2]([C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccnc1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(-c3cccnc3)nc(-c3cccc(Cl)c3)c2c1
Temperature: 115 °C
Reaction time: 3 h
Yield: 25.5 %

Procedure:
A mixture of 2-chloro-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.0051 mol), described in International Patent Specification WO 00/39082, 3-pyridinyl-boronic acid (0.0077 mol) and Pd(PPh3)2Cl2 (0.001 mol) in sodium carbonate 2M (25 ml) and dioxane (25 ml) was stirred at 115° C. for 3 hours, then cooled, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.02 g of a fraction which was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.7 g (36%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-2-(3-pyridinyl)-6-quinazolinemethanol, mp.178° C.
Reaction SMILES: O=[C:2]1[C:11]([C:12]#[N:13])=[C:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]2[CH2:8][CH2:7][C:6]3C=CC=C[C:5]=3[C:4]=2O1.[H-].[Na+].[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>>[N:14]1([C:10]2[C:9]3[CH2:8][CH2:7][C:6]4[C:5](=[CH:27][CH:26]=[CH:25][CH:29]=4)[C:4]=3[C:29]3[C:25]4[C:9]([CH2:8][C:2]=3[C:11]=2[C:12]#[N:13])=[CH:4][CH:5]=[CH:27][CH:26]=4)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: N#Cc1c(N2CCCC2)c2c(oc1=O)-c1ccccc1CC2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c2c(c3c(c1N1CCCC1)CCc1ccccc1-3)-c1ccccc1C2

Procedure:
A mixture of 2-oxo-4-(pyrrolidin-1-yl)-5,6-dihydro-2H-benzo[h]chromene-3-carbonitrile (292 mg), indanone-2 (132 mg) and NaH (28 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 220-222° C.; IR (KBr) 2204 cm−1 (CN); MS (ESI) 364 (M++2).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:9][C:10]([F:21])([F:22])[O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:2]2[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][CH2:3]2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)o1
Product: OC[C@H]1CC[C@@H](c2ccc(OC(F)(F)F)cc2)O1

Procedure:
{cis-5-[4-(Trifluoromethoxy)phenyl]tetrahydrofuran-2-yl}methanol was prepared from 5-bromofuran-2-carbaldehyde and [4-(trifluoromethoxy)phenyl]boronic acid using a method analogous to that described in footnote 21.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][C:3]1=[O:12]>C(O)(=O)C.[Zn]>[Br:11][C:8]1[CH:9]=[C:10]2[CH2:2][C:3](=[O:12])[NH:4][C:5]2=[N:6][CH:7]=1
Reactant: O=C1Nc2ncc(Br)cc2C1(Br)Br
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Cc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under argon at room temperature, 17.60 g (0.27 mol) of powdered zinc are added in portions to 5 g (13.5 mmol) of the compound obtained in Step A dissolved in 100 ml of acetic acid. After 15 hours' stirring at room temperature, the acetic acid is removed by evaporation under reduced pressure (coevaporation with toluene). The residue, which is taken up in ethyl acetate, is washed once with water; the aqueous phase is washed several times with ethyl acetate. The organic phases are combined, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant: dichloromethane/methanol, 95/5), to obtain the title compound in the form of an orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>>[CH2:20]([N:23]([CH2:24][CH2:25][CH3:26])[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1)[CH2:21][CH3:22]
Reactant: CCCNCCC
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Product: CCCN(CCC)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1 h-indazol-5-yl)-amide (Intermediate 16) and dipropylamine (Aldrich), the title compound was obtained as a white solid.
Reaction SMILES: [N+:1]1([O-])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].F[B-](F)(F)F.[CH3:15][O+:16](C)C>C(Cl)Cl>[OH:16][CH2:15][C:4]1[CH:3]=[C:2]([CH3:8])[N:1]=[C:6]([CH3:7])[CH:5]=1
Reactant: C[O+](C)C
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1cc(CO)cc(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 168.7 %

Procedure:
A solution of 2,6-lutidine N-oxide (41.6 g, 0.337 mol, 1.0 equiv.) in dry DCM (650 mL) was added to a flask containing trimethyloxonium tetrafluoroborate (50.0 g, 0.337 mol, 1.0 equiv.) at room temperature. under a nitrogen atmosphere. The mixture was stirred at room temperature for 3.0 hours, then concentrated in vacuo to give 78 g of crude 4-hydroxymethyl-2,6-dimethylpyridine. The crude product was dissolved in methanol (500 mL) and the solution was heated to reflux under a nitrogen atmosphere, then a solution of ammonium persulfate (24.6 g, 0.101 mol) in water (100 mL) was added dropwise. The mixture was stirred at reflux for 16 hours; TLC indicated complete reaction. Half of the solvents were removed in vacuo, then quenched with 10% NaOH solution to pH approximately 7, and evaporated to dryness. The residue was dissolved in methanol and filtered, the filtrate was concentrated in vacuum, and purified by column chromatography (eluting with methanol: DCM=5-15%) to give the title compound as a white solid. Yield: 24.7 g (52%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(N(CC)CC)C.ClC(OCC)=O.Cl.[C:24](=S)=[S:25]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[C:24]=[S:25])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: S=C=S
Reactant: Nc1ccc(F)c(F)c1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Fc1ccc(N=C=S)cc1F
Temperature: 25 °C
Yield: 70.2 %

Procedure:
3,4-Difluoroaniline (600 g) and 1410 g of triethylamine were mixed and, with ice cooling and stirring, 389 g of carbon disulfide was dropped in during 2.5 hours. The mixture was stirred at the same temperature for 2 hours more whereupon crystals gradually appeared. The mixture was gradually warmed up to the room temperature, stirred for 2 hours, and kept in a refrigerator for two nights. Chloroform (2 liters) was added to the reaction mixture in which crystals were solidified, the mixture was stirred to make it suspended, and ethyl chloroformate was dropped in at 10° C. (inner temperature) during 2 hours. The mixture was stirred 3.5 hours more at room temperature. After the reaction, the reaction solution was poured over into ice water, the mixture was made weekly acidic with concentrated hydrochloric acid, and the chloroform layer was collected. This was washed with water, dried and concentrated and the residue was purified by a column chromatography (n-hexane/silica gel) to give 558.6 g of 3,4-difluorophenyl isothiocyanate in colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:27][CH2:28][N:29]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=3)[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-(4-fluorophenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=401.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([C:15]1[N:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:18]=[CH:17][C:16]=1[C:24]([OH:26])=O)#[N:14].CN>CN(C=O)C>[C:13]([C:15]1[N:19]([C:20]([CH3:21])([CH3:22])[CH3:23])[N:18]=[CH:17][C:16]=1[C:24]([NH:3][CH3:1])=[O:26])#[N:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)n1ncc(C(=O)O)c1C#N
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(C(C)(C)C)c1C#N
Temperature: 25 °C
Yield: 45.3 %

Procedure:
Carbonyldiimidazole (2.5 grams, 0.015 mole) was added to a solution of 5-cyano-1-tert-butyl-1H-pyrazole-4-carboxylic acid (2.0 grams, 50.01 mole) in DMF. The solution was stirred at room temperature for twenty minutes. Aqueous methylamine (1.5 ml, 0.015 mole) was added and the reaction mixture was stirred at room temperature for 16 hours, then poured into ice-water. The product precipitated and was collected, dried, and recrystallized from ethanol, yielding 1.4 grams of 5-cyano-1-tert-butyl-N-methyl-1H-pyrazole-4-carboxamide, m.p., 164°-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.O=[C:11]([C:17](OCC)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:9]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17](=[O:18])[NH:8]2
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1cccc(Cl)c1N
Solvent: CCO
Product: CCOC(=O)c1nc2c(Cl)cccc2[nH]c1=O
Temperature: 25 °C
Yield: 56.5 %

Procedure:
10.5 g (73.6 mmol) of 3-chloro-1,2-phenylenediamine and 12.8 g (73.5 mmol) of diethyl ketomalonate were dissolved in ethanol, and the solution was heated to reflux for 3 hours. While heating to reflux, ethanol was added thereto until precipitated crystals dissolved. The reaction mixture was cooled to room temperature, and then precipitated crystals were separated by filtration. The filter cake was washed with cold ethanol, and then dried, to obtain 10.5 g (yield: 51%) of ethyl 5-chloro-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as pale yellow acicular crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[CH3:11].[CH3:13][N:14](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[CH:6][C:5]=1[CH3:11]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C#N)cc1C
Temperature: 100 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid methyl ester (108 g, 471 mmol) in N,N-dimethylformamide (41) under a nitrogen atmosphere was added zinc (II) cyanide (88.5 g, 753.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (65 g, 56.60 mmol). The reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with toluene and the phases were separated. The aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine and saturated aqueous ammonium hydroxide, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:5) to give 4-cyano-2-methylbenzoic acid methyl ester (73 g, 89% yield). 1H NMR (400 MHz, CDCl3): 7.78 (d, 1H), 7.52 (m, 2H), 3.92 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][CH2:12][C@@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH3:14])(=[O:26])=[O:25]
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A solution of (S)-benzyl(1-hydroxypropan-2-yl)carbamate (400 g, 1.91 mol) and triethylamine (270 g, 2.67 mol) in methylene chloride (2.4 L) was cooled to 0° C. To this mixture was added methanesulfonyl chloride (263 g, 2.30 mol) at an internal temperature of 5° C. or below. Subsequently, the resulting reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting materials by TLC, to the reaction mixture was added purified water. The resulting organic layer was partitioned, washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the target product as a yellow solid (519 g, yield 94.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:24])[S:12][C:13]=2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:24][C:11]2[S:12][C:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[O:32])=[CH:29][CH:28]=1)#[N:26]
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(C#N)cc3)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 26.8 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 6 and p-cyanobenzoyl chloride prepared in the step 1 of Example 13 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1-10:1) to obtain a product as a yellow solid in a yield of 26.8%, mp: 190-192└. 1H-NMR (CDCl3, 400 MHz) δ: 3.80 (3H, s, OCH3), 4.32 (2H, s, CH2), 6.75 (2H, d, J=8.72 Hz, ArH), 7.25 (2H, d, J=8.68 Hz, ArH), 7.37 (2H, d, J=8.68 Hz, ArH), 7.59 (2H, d, J=8.40 Hz, ArH), 7.82 (2H, d, J=8.40 Hz, ArH), 8.19 (2H, d, J=8.72 Hz, ArH); EI-MS m/e (%): 470.1 (M+, 100), 130.0 (76); HREI-MS Calcd. for C25H18N4O4S: 470.1049. found: 470.1050. Anal. Calcd. for C25H18N4O4S: C, 63.82; H, 3.86; N, 11.91. found: C, 64.16; H, 3.68; N, 12.19.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:39]([CH3:41])[CH3:40])[C:30]3[CH:35]=[CH:34][C:33]4[O:36][CH2:37][O:38][C:32]=4[CH:31]=3)=[O:28])[C:22]3[CH:42]=[CH:43][CH:44]=[CH:45][C:21]=3[N:20]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:19]2=[O:52])=[N:9]1)=O)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:39]([CH3:41])[CH3:40])[C:30]3[CH:35]=[CH:34][C:33]4[O:36][CH2:37][O:38][C:32]=4[CH:31]=3)=[O:28])[C:22]3[CH:42]=[CH:43][CH:44]=[CH:45][C:21]=3[N:20]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:19]2=[O:52])=[N:9]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-[3-(1-Tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(3,4-methylenedioxy-phenyl) acetamide, prepared as in Intermediate 72, (123 mg, 0.175 mmol) and 4N HCl in dioxane (1 mL) is stirred at RT for 3 h. Diethyl ether (20 mL) is added and the resultant mixture stirred vigorously for 20 min. The solids were allowed to settle and the solvent is decanted. This procedure is repeated three times and the final solid dried by concentration in vacuo to afford the titled product (106 mg) as a white solid: 1H NMR (300 MHz, CDCl3) δ7.95 (d, 1H, J=8.3), 7.68 (d, 1H, J=8.5), 7.59 (t, 1H, J=6.8), 7.2-7.5 (m, 11H), 7.12 (t, 1H, J=8.5), 6.94 (d, 1H, J=8.2), 6.84 (dd, 1H, J=15.8, 8.3), 6.03 (s, 2H), 5.00 (m, 1H, J=6.9), 4.40 (m, 1H), 4.24 (t, 2H, J=6.1), 3.92 (dd, 1H, J=16.5, 7.7), 3.83 (dd, 1H, J=16.5, 5.8), 1.08 (m, 6H); Low resolution MS (FAB) m/e 602 (M+); Tr =23.06 min (RP-HPLC, 70% A to 70% C, 30 min).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH:21]([OH:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCC(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1nc2cnc3ccccc3c2n1CCCC(C)=O
Yield: 61 %

Procedure:
The general method described in Step 8 of Example 1 was used to oxidize 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol (3.54 g, 11.4 mmol) with DMSO (1.33 g, 17.1 mmol), oxalyl chloride (1.59 g, 12.5 mmol), and triethylamine (3.45 g, 34.1 mmol) to provide 5-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (2.15 g) as a dark solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[NH:14][C:15]4[N:16]([N:20]=[C:21]([CH3:23])[N:22]=4)[C:17](=[O:19])[CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[NH:14][C:15]4[N:16]([N:20]=[C:21]([CH3:23])[N:22]=4)[C:17](=[O:19])[CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: CC(=O)n1ncc2cc(-c3cc(=O)n4nc(C)nc4[nH]3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nc2[nH]c(-c3ccc4[nH]ncc4c3)cc(=O)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1-acetyl-1H-indazol-5-yl)-2-methyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one (100 mg, crude) in methanol (3 ml) was added a solution of potassium carbonate (45 mg, 0.33 mmol) in water (1 ml), and the mixture was stirred overnight at room temperature. The resulting solution was concentrated under vacuum to give a residue, which was diluted with water (5 ml). The solids were collected by filtration and purified by Prep-HPLC to afford 5-(1H-indazol-5-yl)-2-methyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a white solid (28.7 mg, 7% 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)ccc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
Cis-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.241 g, 5.85 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.234 g, 5.85 mmol) dissolved in water (2.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.358 mL, 5.85 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-20% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.259 g, 61%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.88-2.13 (m, 4H), 2.63-2.83 (m, 2H), 2.99-3.10 (m, 1H), 3.23-3.34 (m, 1H), 3.45 (s, 3H), 3.88-4.00 (m, 1H), 4.35-4.46 (m, 1H), 5.85 (d, 1H), 6.88-7.06 (m, 3H). MS m/z 353 (M+H)+
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8]P(OC)(OC)=O)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[CH:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=O>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19](/[CH:17]=[CH:8]/[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[CH:20][CH:21]=1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 118.3 %

Procedure:
To a solution of tert-butyl P,P-dimethylphosphonoacetate (Fluka, 1.43 g, 6.4 mmol) in THF (40 mL) was added NaH (Alderich, 60%, 536 mg, 13.4 mmol) portionwise at rt over 30 min. Methyl 4-formylbenzoate (Alderich, 1.0 g, 6.09 mmol) was then added and the reaction mixture was stirred at rt for 4 hrs. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, and dried over Na2SO4. The mixture was then concentrated to give the crude 4-((E)-2-tert-butoxycarbonyl-vinyl)-benzoic acid methyl ester (1.89 g, 118%).