Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:14][CH:15]=O.[H-].[Na+].[Cl:19][C:20]1[C:25]2[N:26]=C(S(C)(=O)=O)[N:28]=[CH:29][C:24]=2[CH:23]=[CH:22][N:21]=1>C1COCC1>[Cl:19][C:20]1[C:25]2[N:26]=[C:15]([NH:14][C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=4)=[CH:7][C:2]=3[CH3:1])[N:28]=[CH:29][C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: CS(=O)(=O)c1ncc2ccnc(Cl)c2n1
Reactant: Cc1cc(-c2cnn(C)c2)ccc1NC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 121.1 %

Procedure:
To a cooled (0° C.) suspension of N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 99, 40 mg, 0.186 mmol) in THF (4 mL) was added NaH (60% dispersion in oil, 12 mg, 0.297 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C. and 8-chloro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 97, 59 mg, 0.242 mmol) was added. The reaction mixture was stirred for 18 hours, whilst slowly warming to room temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (30 mL) and DCM (30 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-5% MeOH in EtOAc to give the title compound (79 mg, 97%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Br:5]C(C=O)[CH:7]=[O:8].[CH3:11][C:12](C)=O>>[BrH:5].[NH2:1][C:2]1([CH:7]=[O:8])[NH:4][CH:12]=[CH:11][S:3]1
Reactant: NC(N)=S
Reactant: CC(C)=O
Reactant: O=CC(Br)C=O
Product: Br
Product: NC1(C=O)NC=CS1
Temperature: 25 °C

Procedure:
Thiourea (33 g, 0.44 mol) was added to a solution of 2-bromo-1,3-propanedial (66 g, 0.44 mol) in acetone (1 liter) and the resulting mixture was stirred vigorously under reflux for 1 hour. After cooling to room temperature, the solid product was filtered off and dried to give 2-aminothiazolecarboxaldehyde hydrobromide (85 g) as a yellow solid, m.pt. 126° C.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:9]1.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][C:19]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:21])=[CH:9]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: COc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(=O)CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
Triethylamine (1.46 mL, 10.5 mmol) was added to a mixture of 1H-indole-3-propanoic acid (1.36 g, 7.2 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (1.5 g, 6.55 mmol) and 1-hydroxybenzotriazole (1.33g, 7.86 mmol) in tetrahydrofuran (20 mL) and the mixture was stirred at room temperature for 10 min. 1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.89 g, 9.8 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with ethyl acetate. The combined organic fractions were washed with saturated aqueous sodium carbonate and water, dried (MgSO4), and the solvent was evaporated under reduced pressure . The residue was triturated with hexane to give the title compound as a colorless solid (2.1 g, 88%). 1H NMR (360 MHz, CDCl3) δ8.00 (1H, br s), 7.63 (1H, d, J 7.6 Hz), 7.36 (1H, d, J 8.0 Hz), 7.10-7.00 (2H, m), 6.94-6.80 (3H, m), 3.85 (3H, s), 3.80 (2H, t, J 5.0 Hz), 3.52 (2H, t, J 5.0 Hz), 3.14 (2H, m), 2.95 (2H, t, J 5.0 Hz), and 2.77 (4H, m). m/z (ES+) 364 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)(=O)C.[OH-].[Na+].Cl>O1CCCC1>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Oc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Oc1cccc(OCc2ccccc2)c1
Yield: 94.9 %

Procedure:
3-Benzyloxyphenyl acetate (4.84 g, 20 mmol), as prepared in the preceding step, in tetrahydrofuran (50 mL) was treated with 1 N NaOH (30 mL) at room temperature for 3 h. The mixture was acidified with 1 N HCl and extracted with ethyl acetate (3×100 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue purified by flash column chromatography (methylene chloride) to give the title compound as a colorless liquid (3.80 g, 96%).
Reaction SMILES: CS(O[CH2:6][C:7]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:8])(=O)=O.[N-:57]=[N+:58]=[N-:59].[Na+].CN(C)C=O>O>[N:57]([CH2:6][C:7]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:8])=[N+:58]=[N-:59]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCC(C)(COCCCCCCCCCCCCCCCCCCCCCC)COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCCOCC(C)(CN=[N+]=[N-])COCCCCCCCCCCCCCCCCCCCCCC
Temperature: 110 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
After a mixture of 2,2-bis(docosyloxymethyl)propyl methanesulfonate (22.7 g; 27.8 mmol), sodium azide (0.27 g; 83.5 mmol), and dimethylformamide (150 ml) was stirred at 110° C. for 20 h, the reaction mixture was poured into water. Precipitates thus obtained were collected by suction, washed successively with water and acetone, and dried to obtain the title compound (20.8 g; 98%).
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)([O-])=O.[ClH:18]>C(O)(=O)C>[ClH:18].[NH2:1][C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])c1c2ccccc2cc2ccccc12
Agent: Cl
Solvent: CC(=O)O
Product: Nc1c2ccccc2cc2ccccc12

Procedure:
A method as claimed in claim 7, in which 9-nitroanthracene is reacted with hydrated tin chloride and acetic acid in the presence of concentrated HCl to produce an aqueous solution of 9-aminoanthracene hydrochloride salt, and the solution is stirred in air at room temperature while 5% aqueous ammonia solution is added slowly until the pH rises to 1.5 to 2.0, the solution is stirred at this pH for at least 5 minutes and then further 5 aqueous ammonia is added slowly to bring the pH up to the range 5.8 to 6.0 and the stirring is continued at that pH for 3 to 6 hours and then further 5% aqueous ammonia is added to bring the pH into the range 8.5 to 9.0 with continued stirring, and the yellow solid which precipitates out is recovered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[N:32][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:28]3[CH:33]=[N:32][CH:31]=[C:30]([OH:34])[CH:29]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: Oc1cncc(Br)c1
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(O)c3)cnc21

Procedure:
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester is coupled with 5-bromo-pyridin-3-ol to give 6-(5-hydroxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using Suzuki Coupling Method VI.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=2)[N:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:45][C:46]1[CH:50]=[C:49]([Sn](C)(C)C)[S:48][N:47]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:45][C:46]1[CH:50]=[C:49]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=3)[N:7]=2)[S:48][N:47]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(Cl)nn12
Reactant: Cc1cc([Sn](C)(C)C)sn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)sn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A pressure vessel was purged with Ar and charged with tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (5.00 g, 17.6 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.807 g, 0.881 mmol), 2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol). DMF (50 mL) was added, immediately followed by 3-methyl-5-(trimethylstannyl)isothiazole (6.46 g, 24.7 mmol). The reaction mixture was stirred at 100° C. for 1 h. Two more portions of tris(dibenzylideneacetone)dipalladium(0) (0.807 g, 0.881 mmol) and 2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol) were added every hour for the first two hours of stirring. Reaction was then stirred was at 100° C. overnight, cooled to room temperature and concentrated in vacuo. Purification by MPLC (EtOAC/MeOH: 100/0 to 90/10) afforded the title compound (1.80 g, 30% yield). MS m/z=347.1 [M+H]+. Calc'd for C15H18N6O2S: 346.41
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](I)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](B(O)O)=[CH2:27])=[CH:22][CH:21]=1.N12CCCN=C1CCCCC2.O>CN1CCCC1=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[CH2:27])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: C=C(B(O)O)c1ccc(F)cc1
Reactant: Cc1noc(C)c1-c1cc(I)c2[nH]c(=O)[nH]c2c1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(c1ccc(F)cc1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 110 °C

Procedure:
6-(3,5-Dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.28 mmol), 1-(4-Fluorophenyl)vinylboronic acid, pinacol ester (209.59 mg, 0.84 mmol), PEPPSI″-IPr catalyst (19.19 mg, 0.03 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene solution (0.25 ml, 1.69 mmol) were mixed in 1-Methyl-2-pyrrolidinone (6 ml) and Water (3 ml) in sealed in a microwave vial and heated to 110° C. for 30 minutes in a microwave reactor. The reaction mixture was then cooled and partitioned between water and ethyl acetate. The organic layer was washed with water then brine and dried over sodium sulfate. Purification on silica gel (Hexane/EtOAc) followed by preparative HPLC afforded 6-(3,5-dimethylisoxazol-4-yl)-4-(1-(4-fluorophenyl)vinyl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: COC([O:7][CH3:8])N(C)C.C[C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13].P([O-])([O-])([O-])=O>CN(C=O)C.C1COCC1>[CH:8]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:11]=1[C:12]#[N:13])=[O:7]
Reactant: COC(OC)N(C)C
Reactant: Cc1cccc([N+](=O)[O-])c1C#N
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1c(C=O)cccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (13.56 mL, 102 mmol) was added to a solution of 2-methyl-6-nitrobenzonitrile (15.0 g, 92.5 mmol) in anhydrous DMF (60 mL) under nitrogen and was heated at 130° C. for 15 h. Ice water (300 mL) was added, and the resultant dark precipitate was collected by filtration and dried under vacuum. Phosphate buffer (pH 7, 350 mL) and then NaIO4 (40 g, 187 mmol) were added to a solution of the dark precipitate in THF (350 mL) and stirred at rt for 3 h. The mixture was extracted with EtOAc, the combined extract was washed with brine and dried with MgSO4. The filtrate was concentrated and the residue was purified by chromatography on silica using the solven gradient hexanes→EtOAc, to give 3.07 g (19%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J=8.4 Hz, 1H), 8.41 (dd, J=1.2, 7.6 Hz, 1H), 8.62 (dd, J=1.2, 8.4 Hz, 1H), 10.25 (s, 1H).
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23]1>C(O)(=O)C>[Br:1][C:26]1[O:22][CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=1
Reactant: O=C(O)c1ccoc1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(O)c1coc(Br)c1
Temperature: 40 °C

Procedure:
To a stirred solution of pyridinium tribromide (14.3 g, 44.6 mmoles) in acetic acid (20 ml) was added 3-furoic acid (5 g, 44.6 mmoles). The resulting mixture was heated at 40° C. for 16 hours. The acetic acid was evaporated; the residue was dissolved in dichloromethane (50 ml), washed with water (3×50 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by HPLC (gradient: 20% acetonitrile/80% water containing 0.1% trifluoroacetic acid to 80% acetonitrile/20% water at a rate of 1%/min) to afford 5-Bromo-furan-3-carboxylic acid (7) as a white solid. LC/MS System A; Rt=2.52 mins, m/z (ES−)=189/191 (M−H for C5H3BrO3).
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.O.[OH-].[Li+]>O>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]3[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: CCCCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Yield: 136.1 %

Procedure:
(R)-4-methyl-4-(6-(4-pentylcyclohexyloxy)naphthalen-2-yl)oxazolidin-2-one (0.3672 g, 0.0009284 mol) was dissolved in ethanol (5.00 mL, 0.0856 mol) in a capped 40 mL EPA vial equipped with a stir bar. 4.2 M Lithium hydroxide, monohydrate in water (2.00 mL) was added and the mixture was heated at 80° C. overnight. TLC analysis showed that the reaction was complete. The mixture was concentrated to dryness under vacuum. The product was dissolved in methylene chloride (5 mL) and washed with water (2×5 mL). The layers were separated (phase separator cartridge) and the organic layer was concentrated to dryness and purified by HPLC to give 0.467 g of the title compound (14% yield). MS: m/z=353.36 [M-NH2]+. 1H NMR (400 MHz, MeOD) δ 0.90-0.98 (m, 3 H), 1.10-1.24 (m, 1 H), 1.26-1.54 (m, 8 H), 1.58-1.74 (m, 2 H), 1.80 (s, 3 H), 1.86-1.95 (m, 2 H), 2.03-2.13 (m, 2 H), 2.20-2.29 (m, 2 H), 3.80-3.87 (m, 1 H), 3.91-3.97 (m, 1 H), 4.36-4.79 (m, 1 H, 1:1 ratio), 7.17-7.26 (m, 1 H, 1:1 ratio), 7.28 (d, J=2.51 Hz, 1 H), 7.53 (dd, J=8.78, 2.01 Hz, 1 H), 7.80-7.90 (m, 3 H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:6]=2[CH:24]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36](=[O:39])[NH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O.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.C(O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:34]=[CH:35][C:36](=[O:39])[NH:37][CH:38]=4)=[CH:24][C:6]2=3)=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2ccc(=O)[nH]c2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)[nH]c3)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Temperature: 100 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
A mixture of (R)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (40.2 mg, 0.1 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (44.2 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), cesium carbonate (98 mg, 0.3 mmol), toluene (2 mL), ethanol (1 mL) and water (3 drops) was stirred at 100° C. for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with water (3*20 mL), brine (3*20 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuum, and then the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give (R)-5-(6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2(1H)-one as a white solid (20 mg, 48%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>ClCCl>[OH:1][C:2]1[CH:7]=[N+:6]([O-:20])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(O)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
To a suspension of methyl 5-hydroxypyridin-2-carboxylate (5.30 g) in dichloromethane (75 ml), m-chloroperbenzoic acid (>65%, 11.0 g) is added under ice-cooling, and the mixture is stirred at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure. The residue is suspended in ethyl acetate and collected by filtration to give the title compound (4.62 g). Mother liquor is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent: chloroform to methanol/chloroform=1/5). The resulting solid is suspended in ethyl acetate/diethyl ether and collected by filtration to give the title compound (0.68 g).
Reaction SMILES: [CH2:1]([S:5][C:6]([CH3:35])([CH3:34])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH:12]([CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]1)[C:13]([S:16]CC1C=CC(OC)=CC=1)([CH3:15])[CH3:14])[CH2:2][CH2:3][CH3:4].FC(F)(F)S(O)(=O)=O.O1CCCC1.Cl.O1CCOCC1>CCOCC>[CH2:1]([S:5][C:6]([CH3:34])([CH3:35])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH:12]([CH2:26][N:27]1[CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH2:32]1)[C:13]([SH:16])([CH3:15])[CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSC(C)(C)CNCCNC(CN1CCC(C)CC1)C(C)(C)SCc1ccc(OC)cc1
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCCCSC(C)(C)CNCCNC(CN1CCC(C)CC1)C(C)(C)S
Yield: 29.5 %

Procedure:
A solution of Compound (32) (HCl salt) (2.5 g; 4.2 mmol) in a 1M trifluoromethanesulfonic acid in tetrahydrofuran (42 ml; 42 mmol) was stirred for 1 hour under cooling. The reaction mixture was combined with ether and extracted with 2N hydrochloric acid five times. The aqueous layer was adjusted to pH 10 with potassium carbonate and extracted with chloroform three times. The chloroform extract was washed with a saturated aqueous sodium chloride solution two times, dried over anhydrous sodium sulfate and concentrated. Under cooling, a 4N hydrogen chloride in dioxane (7 ml; 28 mmol) was added thereto, followed by concentration. The residue was purified by silica gel column chromatography with a mixture of chloroform and methanol (20:1) as an eluting solvent to give Compound (33) (HCl salt) (0.5 g; yield, 24%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:7]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (commercially available) (1.0 eq.), 1-ethynyl-4-methylbenzene (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by stirring in hot ether/hexane mixtures and filtered to give 3-chloro-5-(p-tolylethynyl)picolinonitrile.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[N:16]1([C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][N:18]=[CH:17]1.C(N(CC)CC)C>ClCCl>[O:8]([C:24]1[CH:25]=[CH:26][C:21]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:22][CH:23]=1)[S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2]
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc(-n2ccnc2)cc1)C(F)(F)F
Reaction time: 18 h

Procedure:
Triflic anhydride (2.82 g) was added dropwise to a mixture of 4-(1-imidazolyl)phenol (Aldrich Chemical Company) and triethylamine (1.1 g) in dichloromethane (30 ml). The mixture was stirred for 18 hours. The mixture was evaporated and the residue partitioned between diethyl ether and water. The organic phase was separated, washed with water, dried (MgSO4) and evaported. The residue was triturated with cyclohexane to give crude 4-(1-imidazolyl)phenyl triflate (1.7 g) as a solid, which was used without further purification; m/Z 293 (M+H).