Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.O=[C:24]1[C@H:30]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28][C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[NH:25]1>C1(C)C=CC=CC=1>[S:10]=[C:24]1[CH:30]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28][C:27]2[CH:42]=[CH:43][CH:44]=[CH:45][C:26]=2[NH:25]1
Reactant: O=C(N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C(NC1CCc2ccccc2NC1=S)OCc1ccccc1
Yield: 104.3 %

Procedure:
Add Lawesson's Reagent (6.52 g, 16.11 mmol) to a solution of benzyl N-[(3R)-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (10.0 g, 32.22 mmol) in toluene (120 mL) and heat the reaction under nitrogen at 100° C. for 2.5 hours. Allow the reaction to cool and collect the precipitate by filtration. Wash (ether) the cake and dry it in a vacuum oven to give the title compound (5.5 g, 16.8 mmol). Concentrate the filtrate under reduced pressure and purify it by flash chromatography (30% hexane/CH2Cl2 to 100% CH2Cl2) to give the title compound (3.48 g, 10.7 mmol). The compound is partially racemized. The total yield of the title compound is 85%: MS (m/z): 327 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18]
Reactant: O=C1Nc2cccc3c2[C@@]1(CCCCBr)CCC3
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cccc3c2[C@@]1(CCCCN1CCc2ccccc2C1)CCC3
Yield: 100 %

Procedure:
(S)-2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (120 mg, 0.40 mmol), 1,2,3,4-tetrahydroisoquinoline (59 mg, 0.44 mmol), and potassium carbonate (83 mg, 0.60 mmol) in anhydrous N,N-dimethylformamide (1 ml) were stirred at room temperature for 2 days. To the reaction mixture obtained was added ethyl acetate (80 ml), which was then washed with water and saturated saline solution. After drying with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain a product. The product obtained was separated and purified by means of silica gel column chromatography, whereby 150 mg (0.40 mmol, yield 100%) of the above-described object compound could be obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[OH:11].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([OH:11])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)c(O)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 2-chloro-5-nitrophenol (20.0 g, 115.2 mmol) in ethanol (150 ml) and water (150 ml) was added iron powder (32.2 g, 576.2 mmol) and ammonium chloride (32.1 g, 599.3 mmol). The mixture was heated at reflux for two hours, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/9:1) gave 5-amino-2-chloro-phenol (15.85 g, 96%) as a white solid.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:20]=1)([CH2:13][CH2:14][C:15]([O:17]C)=O)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])#[N:5].Cl>C1(C)C=CC=CC=1>[C:9]([CH:8]1[CH2:7][C:6]([C:4]#[N:5])([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:20]=2)[CH2:13][CH2:14][C:15]1=[O:17])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC3CCCC3)c2)CCC1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium methoxide (350 mL, 1.55 mol, 25% w/w in methanol) in toluene (2.45 L) heated to 80° C. under a nitrogen atmosphere was added a solution of dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (350.0 g, 0.87 mol) in toluene (1.05 L) over 10 min. The reaction was heated to 85° C. by distilling away 250 mL of solvent and was vigorously stirred under nitrogen for 2 hours. The reaction was cooled to 50° C. and was quenched with 3N (aq) HCl (700 mL, 2.1 mol). The organic layer was isolated, was washed once with deionized water (700 mL) and once with brine (700 mL). The organic layer was concentrated via low vacuum distillation to afford crude 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-one in toluene. This was dissolved in 4.2 L of dimethyl sulfoxide and used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[N+:17]([O-])=O)[CH:5]=[CH:6][CH:7]=1.C.O.NN>CO>[NH2:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:13]#[N:14]
Reactant: N#Cc1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Agent: NN
Solvent: CO
Solvent: O
Product: N#Cc1ccc(Nc2cccc(Br)c2)c(N)c1
Temperature: 80 °C

Procedure:
To a solution of compound C (1 g, 3.14 mmol) in methanol (10 mL) was added anhydrous FeCl3 (100 mg, 0.65 mmol) and charcoal (100 mg). The mixture was stirred at 60° C. and at that temperature hydrazine hydrate (10 mL) was added slowly where after the temperature was raised to 80° C. for 1.5 h. The reaction mixture was cooled to RT, filtered through a small pad of celite and washed with methanol. The organic layer was concentrated and washed with water, to give light brown solid D (200 mg, 22%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:5]=1>CO>[Cl:3][C:4]1[C:9]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=2)[N:5]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
4N NaOH solution (20 mL) was added to a solution of trans-ethyl 2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanecarboxylate (5.5 g, 14.90 mmol), in Methanol (50 mL) and stirred at RT for 2 h. After completion, the solvent was evaporated and the residue was diluted with water (50 mL), acidified with 4 N HCl solution, extracted with EtOAc (2×50 mL). The combined extracts were washed with water (2×50 L), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to afford trans-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanecarboxylic acid (4.9 g), as a yellow liquid. The crude was carried to next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH2:11].C([Sn](CCCC)(CCCC)[CH2:18][O:19][CH3:20])CCC.CN1C(=O)CCC1.[F-].[K+]>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(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:18][O:19][CH3:20])=[N:6][C:5]=1[NH2:11]
Reactant: CCCC[Sn](CCCC)(CCCC)COC
Reactant: COC(=O)c1ccc(Cl)nc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COCc1ccc(C(=O)OC)c(N)n1
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 63.2 %

Procedure:
A mixture of 2-amino-6-chloro-nicotinic acid methyl ester (1.4 g) described in Manufacturing Example 11-2, tributyl-methoxymethyl-tin (3.1 g) described in Manufacturing Example 11-3-1, tetrakis(triphenylphosphine)palladium(0) (440 mg), and NMP (20 mL) was stirred for 3.5 hours at 130° C. The reaction solution was allowed to cool, an aqueous potassium fluoride solution and ethyl acetate were added thereto under ice cooling, after which the reaction mixture was filtered through Celite. The organic layer was washed with saturated brine, after which the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the titled compound (0.93 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Br:24][C:25]1[C:26](F)=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Cl:31][C:29]1[CH:30]=[C:25]([Br:24])[C:26]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:27][CH:28]=1
Reactant: Fc1ncc(Cl)cc1Br
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(Cl)cc4Br)cc3n2C)c1
Yield: 90.8 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (9.40 g, 30.0 mmol), 3-bromo-5-chloro-2-fluoropyridine (6.90 g, 33.0 mmol), copper iodide (0.57 g, 3.00 mmol), 1,10-phenanthroline (0.54 g, 3.00 mmol), cesium carbonate (29.3 g, 90 mmol) and DMF (90 mL) to obtain the title compound (13.7 g, 91%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9]O)=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[Cl:23][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(F)ccc1OCCCO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(F)ccc1OCCCCl
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred mixture of 12.6 parts of 3-(4-fluoro-2-nitrophenoxy)propanol, 0.9 parts of N,N-dimethylformamide and 150 parts of trichloromethane were added dropwise 8.36 parts of thionyl chloride and stirring was continued for 1 hour at room temperature. The whole was further stirred and refluxed for 3 hours. The reaction mixture was evaporated under methylbenzene. The residue was stirred in petroleumether. The product was filtered off and dried, yielding 7.41 parts (55%) of 1-(3-chloropropoxy)-4-fluoro-2-nitrobenzene; mp. 143.3° C. (intermediate 25).
Reaction SMILES: C(N1C2C(=CC=C(N)C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C.[C:22]([NH:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1C1C=NN(C3CC3)C=1)[N:32]([C:44]([O:46][CH:47]([CH3:49])[CH3:48])=[O:45])[CH2:31][C@H:30]([CH3:50])[N:29]2[C:51](=[O:53])[CH3:52])(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:44]([O:46][CH:47]([CH3:48])[CH3:49])=[O:45])[CH2:31][C@H:30]([CH3:50])[N:29]2[C:51](=[O:53])[CH3:52])(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Agent: CC(=O)N1c2cc(N)ccc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)Nc1ccc2c(c1)N(C(C)=O)[C@@H](C)CN2C(=O)OC(C)C

Procedure:
Isopropyl (S)-6-acetamido-4-acetyl-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure described above for isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 235). MS (ESI, pos. ion) m/z 356 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH3:16])[C:6]1=[O:7])[CH3:4].Cl[CH2:18][CH2:19][CH2:20][CH2:21][P:22]([O:27][CH2:28][CH3:29])(=[O:26])[O:23][CH2:24][CH3:25]>>[CH3:1][O:2][CH:3]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:18][CH2:19][CH2:20][CH2:21][P:22](=[O:26])([O:27][CH2:28][CH3:29])[O:23][CH2:24][CH3:25])[CH:11]=[N:10][C:9]=2[N:8]([CH3:16])[C:6]1=[O:7])[CH3:4]
Reactant: COC(C)n1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CCOP(=O)(CCCCCl)OCC
Product: CCOP(=O)(CCCCn1cnc2c1c(=O)n(C(C)OC)c(=O)n2C)OCC

Procedure:
The title substance was prepared from 1-methoxyethyl-3-methylxanthine and diethyl 4-chlorobutanephosphonate analogously to Example 4 and crystallized from diisopropyl ether.
Reaction SMILES: CN.CO.[CH2:5]([N:7](CC)CC)C.O1CCCC1.Cl[C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]([S:26][CH3:27])[N:19]=1>O>[CH3:5][NH:7][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]([S:26][CH3:27])[N:19]=1
Reactant: CCN(CC)CC
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: CN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(SC)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
3 ml of a methylamine-methanol solution, and 246 mg of triethylamine were added to a tetrahydrofuran (10 mL) solution containing 150 mg of 4-chloro-2-(methylsulfanyl)pyrimidine-5-carbonitrile, and the mixture was stirred for 30 minutes at room temperature. After adding water, the solution was extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. After concentration, 134 mg of a white solid was obtained as a subject compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:27][CH2:28][NH:29]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:27][CH2:28][NH2:29]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
A solution of 3-{2-(2-tert-butoxycarbonylamino-ethyl)-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester (0.90 g, 1.77 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with TFA (5.0 mL) and water (0.2 mL). The resulting solution was allowed to warm gradually to ambient temperature. After 18 h, the mixture was concentrated. The residue was partitioned between CH2Cl2 (30 mL) and 5N NaOH (2 mL), and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organics were dried (K2CO3) and concentrated to a residue, which was purified by silica gel chromatography (CH2Cl2/MeOH/NH4OH, 8/2/0.05) to afford the title compound as a colorless oil (0.42 g, 58%). 1H NMR (400 MHz, CDCl3): δ 2.34 (s, 3H), 2.52 (t, 2H, J=7.8 Hz), 2.81 (t, 2H, J=7.8 Hz), 2.91 (t, 4H, J=6.4 Hz), 3.06 (t, 2H, J=7.3 Hz), 3.60 (s, 3H), 4.20 (t, 2H, J=6.8 Hz), 6.68 (br s, 1H), 6.71 (d, 1H, J=8.3 Hz), 7.01 (d, 1H, J=8.3 Hz), 7.37-7.39 (m, 3H), 7.89-7.92 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=O)=O)=CC=1>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:33][CH:34]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(Cl)cc2)cc1
Product: O=C(N[C@H]1CCN(CCCc2ccc(Cl)cc2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 32.2 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 3-(4-chlorophenyl)propyl p-toluenesulfonate (0.97 g) were reacted under the same conditions as in Example 6 to give (S)-N-(1-(3-(4-chlorophenyl)propyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.26 g), melting point 117-119° C.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[B:16]([OH:17])[O:15][CH2:14][C:13]=3[CH:18]=2)=[CH:6][C:5]=1[C:21]([O:23]C)=O)(=[O:3])[NH2:2].[OH-].[Na+].Cl>CO>[OH:17][B:16]1[C:12]2[CH:11]=[CH:10][C:9]([O:8][C:7]3[CH:6]=[C:5]4[C:4](=[CH:20][CH:19]=3)[C:1](=[O:3])[NH:2][C:21]4=[O:23])=[CH:18][C:13]=2[CH2:14][O:15]1
Reactant: COC(=O)c1cc(Oc2ccc3c(c2)COB3O)ccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(=O)c2cc(Oc3ccc4c(c3)COB4O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
A mixture of 5-(4-Carbamoyl-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole (560 mg, 1.71 mmol) and 1 M NaOH (5 mL) in methanol (15 mL) was stirred at room temperature for 10 min. The mixture was acidified with 6 M HCl, and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with ethyl acetate to give 5-(1,3-Dihydro-1-hydroxy-2,1-benzoxaborol-5-yloxy)isoindoline-1,3-dione (380 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:21][CH2:22][CH2:23][Cl:24])[C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:17]=1
Reactant: ClCCCBr
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(CCCCl)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 7 parts of 6-chloro-1,3-dihydro-1-phenyl-2H-benzimidazol-2-one in 67.5 parts of N,N-dimethylformamide is added portionwise 1 part of a sodium hydride dispersion 78%. After stirring for 2 hours at room temperature, there are added dropwise (slowly) 4.75 parts of 1-bromo-3-chloropropane. Upon completion, stirring is continued first for two hours at room temperature and further for one hour at 60° C. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5-chloro-1-(3-chloropropyl)-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one as a residue.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.[CH3:12]O>C(Cl)Cl>[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:12])=[O:8])=[CH:5][N:4]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CO
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
Hydrochloric acid (gas) was bubbled through a solution of 6.11 g (38.8 mmol) of 6-chloronicotinic acid in approximately 350 ml of methanol. The resultant reaction mixture was reacted for approximately two hours at reflux temperature, then cooled to room temperature and concentrated in vacuo to provide a white residue. This residue was redissolved in methylene chloride and the resultant solution was washed with a saturated sodium bicarbonate solution. The organic portion was dried over sodium sulfate, filtered and then reduced to dryness in vacuo to provide 7.28 g of a tan solid. This solid was crystallized from pentane, followed by recrystallization from hexane to provide the desired titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2C(OC(C)(C)C)=O)[C:17]3=[O:22])=[O:10])=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].O1CCOCC1.Cl>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[C:17]3=[O:22])=[O:10])=[CH:4][C:3]=1[C:36]([F:39])([F:37])[F:38]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1ccc2c(NC(=O)Cc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)c(C(F)(F)F)c1)Nc1cccc2c(=O)n(C[C@@H]3CCCN3)ccc12
Reaction time: 8 h

Procedure:
Into a 20 ml reaction vessel was combined (S)-tert-butyl 2-((5-(2-(4-chloro-3-(trifluoromethyl)phenyl)acetamido)-1-oxoisoquinolin-2(1H)-yl)methyl)pyrrolidine-1-carboxylate (20.0 mg, 0.0000355 mol) and 1,4-dioxane (5 mL, 0.06 mol). Hydrogen chloride (0.016 g, 0.00044 mol) as a 2.0M solution in ether was added dropwise. The reaction was allowed to stir overnight. A white preciptate had formed and was filtered, washed with ether, and dried. The product was dissolved in diethylamine and DMSO (1 mL) and was purified by HPLC using a Phenomenex AXIA packed C18 column (100×21.2 10 micron) at pH 10. The combined pure fractions were reduced in vacuo to yield the title compound as a white solid. LC/MS M+H=464.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1>O=P(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc2cc(Cl)ccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccc2cnc(-c3ccccc3)nc2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
7-Chloro-2-phenylquinazolin-4(3H)-one (40 mg, 0.16 mmol) was suspended in POCl3 (2 mL) and heated to 50° C. with stirring for 24 h. Later the reaction was heated to 90° C. for 16 h. With minimum exposure to moisture, the crude mixture was evaporated to dryness under reduced pressure and treated with 2 M NH3/i-PrOH (8 mL) with cooling on ice-H2O bath under Ar. The mixture was partitioned between DCM and H2O and the organic layer was washed (H2O, satd NaHCO3 and brine), dried (Na2SO4) to afford crude material which was used directly in the following de-chlorination step. The crude material (31 mg, 0.113 mmol) and tosylhydrazide (63 mg, 0.34 mmol) were dissolved in anh CHCl3 (10 mL) and heated at 60° C. (overnight, bath temperature) and, then refluxed for 4 h. The solvent was removed under reduced pressure and the solid residue was heated under Ar in anh. PhMe (10 mL) and anh ClCH2CH2Cl (5 mL) at 80° C. (bath temperature) for 63 h: The reaction was cooled to rt and a pale yellow precipitate was collected by filtration and washed with PhMe and DCM (2×). The collected solid in aq Na2CO3 (10%, 10 mL) was placed in a preheated bath at 90° C. After stirring at the temperature for 45 min, the reaction was cooled and left standing at rt overnight. The crude reaction mixture was extracted with DCM (3×), washed (H2O, brine), dried (Na2SO4), concentrated under reduced pressure, and purified by flash chromatography (silica gel, 100:0→10:1 EtOAc:hexanes) to afford the title compound as a light orange solid; 1H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.63-8.56 (m, 2H), 8.09 (d, J=0.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.58-7.50 (m, 4H).