Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([OH:14])(=O)[CH3:12]>N1C=CC=CC=1>[O:14]=[C:11]1[C:12]2[CH:8]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=[C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][N:7]12
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: O=C(O)c1ccc2nc3ccccc3c(=O)n2n1

Procedure:
A precipitate is obtained when a mixture of methyl anthraniliate (4.78 g, 31.6 mmol), 6-chloropyridazine-3-carboxylic acid (5.0 g, 31.6 mmol) and 50 ml of acetic acid is heated at reflux for 21 hrs; m.p. 246°-50° C. This crude material is recyrstallized from pyridine giving the anlytical sample, m.p. 239°-43° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.BrC1C=CC(I)=C(S(C)(=O)=O)C=1.[Cl:30]C1C=CC(B(O)O)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:30])=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Agent: CS(=O)(=O)c1cc(Br)ccc1I
Product: CS(=O)(=O)c1cc(Br)ccc1-c1ccc(Cl)cc1

Procedure:
Following the general method as outlined in Intermediate 203, starting from 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202) and 4-chlorophenylboronic acid, the title compound was obtained as a beige solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:12]=1.[I:22]I.O>O1CCCC1.C(OCC)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][C:11]2[CH:10]=[N:9][CH:8]=[C:7]([I:22])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: II
Reactant: Fc1ccc(C#Cc2cncc(Br)c2)cc1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C#Cc2cncc(I)c2)cc1
Reaction time: 1 h
Yield: 53 %

Procedure:
Add a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (81 mL, 161.7 mmol) to a solution of 3-bromo-5-(4-fluorophenylethynyl)-pyridine, (prepared essentially as described in PREPARATION 24), (40.5 g, 147 mmol) in anhydrous tetrahydrofuran (400 mL) at room temperature under nitrogen. Stir for 1 h, add a solution of iodine (41 g, 161.7 mmol) in anhydrous tetrahydrofuran (250 mL) and stir for an additional 16 h. Add water (200 mL) to the reaction mixture, dilute with diethyl ether (400 mL) and separate the layers. Sequentially wash the organic layer with a 10% aqueous solution of sodium thiosulfate (150 mL), water (200 mL) and an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 15:1 hexanes:ethyl acetate, to give the title compound as a pale yellow solid (25.4 g, 53%).
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:12][C:13]([N:15]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]([CH3:20])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([O:51][C:52](=[O:70])[CH2:53][C@H:54]([NH2:69])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[CH:63]=2)=[CH:58][CH:57]=1)[CH3:50]>C1COCC1.C(#N)C.O>[CH2:49]([O:51][C:52](=[O:70])[CH2:53][C@H:54]([NH:69][C:17](=[O:19])[CH:16]([N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:20])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[CH:63]=2)=[CH:58][CH:57]=1)[CH3:50]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)C(C)C(=O)O
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(C)N(CC(=O)OCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
To a suspension of 2-(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-propionic acid TFA salt (197 mg, 0.714 mmol) in THF (10 ml) at room temperature is added EDCl (219 mg, 1.142 mmol) and HOBT (164 mg, 1.071 mmol). The mixture is stirred at room temperature for 10 mins and then was added a solution of (R)-3-amino-4-(3′-chloro-biphenyl-4-yl)-butyric acid ethyl ester (202 mg, 0.571 mmol) in THF and TEA (0.199 ml, 1.428 mmol). The mixture is stirred at room temperature. Reverse phase HPLC [30 to 90% ACN—H2O (0.1% TFA) over 10 min by X-Bridge phenyl column] give the title compound (290 mg, 71% yield). LCMS (condition B): 575 (M+1); retention time=1.52 min.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:3]([C:5]2[CH:9]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[NH:7][N:6]=2)=[O:4])[CH2:26][CH2:27]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n[nH]1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC2CCOCC2)n[nH]1
Yield: 99 %

Procedure:
As described for example 14e, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.22 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine to the title compound (85 mg, 99%), which was obtained as a colorless oil. MS: m/e=384.2 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:15]=1Cl.[H-].[Na+]>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:15]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: N#Cc1ccc2nc(S)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)sc2c1
Yield: 99.4 %

Procedure:
The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-6-carbonitrile (241) (960 mg, 5.0 mmol), 1,2,3-trichloro-5-nitrobenzene (Acros, 1.13 g, 5.0 mmol) and NaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 260 (1.9 g, 99%) was obtained as a yellow solid.
Reaction SMILES: C([O:14][C:15]([C:17]1[O:18][C@@H:19]([C:45](=[O:51])[N:46]([CH3:50])[CH2:47][CH2:48][CH3:49])[C@H:20]([NH:41][C:42](=[O:44])[CH3:43])[C@@H:21]([NH:23][C:24]([NH:33]C(OC(C)(C)C)=O)=[N:25]C(OC(C)(C)C)=O)[CH:22]=1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>ClCCl>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[C:42]([NH:41][C@H:20]1[C@H:19]([C:45](=[O:51])[N:46]([CH3:50])[CH2:47][CH2:48][CH3:49])[O:18][C:17]([C:15]([OH:16])=[O:14])=[CH:22][C@@H:21]1[NH:23][C:24]([NH2:33])=[NH:25])(=[O:44])[CH3:43]
Reactant: CCCN(C)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]1NC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](NC(=N)N)[C@H]1NC(C)=O
Reaction time: 3 h

Procedure:
(4S,5R,6R)-5-Acetylamino-4-[2,3-bis(tert-butoxycarbonyl)-guanidino]-6-(methylpropylcarbamoyl)-5,6-dihydro-4H-pyran-2-carboxylic acid benzhydryl ester (0.11 g) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and left to stand for 3 hours. The solvent was removed in vacuo and the residue was triturated using diethyl ether. The solid was collected by filtration and dried to give the title compound as a white solid. (0.061 g) 1H NMR (250 MHz, D2O) 6.00 (1H, d, J=4Hz), 5.34 (1H, d, J=6.3Hz), 4.43-4.29 (2H, m) 3.56-3.13 (2H, m), 3.13,2.93 (3H, 2xs), 2.00 (3H, s), 1.79-1.44 (2H, m), 0.88 (3H, m); Mass analysis:C16H24F3N5O7. Required C, 42.20; H, 5.31; N15.38. Found C, 42.24; H, 5.45; N, 15.09; Mass Spec (Low resolution):MH+ =342.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([Cl:13])=[CH:11][C:10]([F:14])=[C:9]([C:15]3[C:16](=[O:26])[N:17]([CH3:25])[C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:32](O)[CH3:33]>>[Cl:13][C:12]1[C:6]2[O:5][C:4]([C:1]([O:3][CH2:32][CH3:33])=[O:2])=[CH:8][C:7]=2[C:9]([C:15]2[C:16](=[O:26])[N:17]([CH3:25])[C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)=[C:10]([F:14])[CH:11]=1
Reactant: CCO
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C(=O)O)cc23)c1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Yield: 99 %

Procedure:
0.08 g (0.21 mmol) of 3-(2-carboxy-7-chloro-5-fluorobenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 10 ml of ethanol, and 4.0 mg (0.04 mmol) of sulfuric acid was added thereto, followed by refluxing for 2 hours. Ethanol was distilled off under reduced pressure. Then, the obtained residue was poured into water and extracted with diethyl ether. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Diethyl ether was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.09 g (yield: 99%) of the desired product. Melting point: 118-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.[OH-].[Na+].[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: Oc1ccnc2cc(Br)cnc12
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1O
Temperature: 90 °C

Procedure:
A mixture of 7-bromo[1,5]naphthyridin-4-ol (33 g, 0.147 mol) and fuming nitric acid (350 mL) was heated at reflux (90° C. internal reaction vessel temperature) for 3 hours. The reaction mixture was cooled to 50° C., poured over 1 L of ice and neutralized to pH 2-3 with a solution of 50% aqueous sodium hydroxide. The resulting precipitate was filtered, washed with water, and dried over vacuum for 3 days to yield 25.1 g of 7-bromo-3-nitro[1,5]naphthyridin-4-ol as a yellow crystalline solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[Cl:23][C:24]1[C:33]([CH:34]=O)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][S:27][C:26]=2[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[Cl:23][C:24]1[C:33]([CH2:34][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][S:27][C:26]=2[CH:25]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1nc2c(cc1Cl)SCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4nc5c(cc4Cl)SCC(=O)N5)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To 12 mL of a chloroform solution containing 609 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 414 mg of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde, 121 mg of acetic acid was added, and stirred at room temperature for 3 hours. To the reaction mixture, 618 mg of sodium triacetoxyborohydride was added, and stirred for 10.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform: methanol=10:1], to give 0.73 g of 1-(2-(4-((7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a pale yellow foam. To 3 mL of an ethyl acetate solution containing 0.30 g of 1-(2-(4-((7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one, 2 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature. The resulting solid was filtered to give 300 mg of 1-(2-(4-((7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one hydrochloride as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([S:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:16])=[O:15])[CH:5]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1>[C:23]([O:22][C:20]([CH2:19][CH2:18][CH2:17][S:14]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:7]=1)[C:3]([OH:27])=[O:2])(=[O:15])=[O:16])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCCC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CCCS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(3-tert-butoxycarbonyl-propane-1-sulfonyl)-5-trifluoromethyl-benzoic acid methyl ester (100 mg, 0.244 mmol) in dioxane (1 mL) was added water (1 mL) and lithiumhydroxide monohydrate (11.2 mg, 0.268 mmol) and the resulting suspension stirred at room temperature for 4 hours. The reaction mixture was acidified with 1M aqueous hydrochloric acid and extracted with EtOAc (30 mL) and the layers were separated. The aqueous layer was extracted a second time with EtOAc (30 mL). The organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. Colorless solid (76 mg, 78.7%). MS (ESI−): m/z=395.08 ([M−H]−).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][N:13]([CH3:14])[C:7]2=[N:6][C:5]=1[CH3:15].Br.Br.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C(=O)C>[NH:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:2][CH2:3][C:4]2[C:9](=[O:10])[N:8]3[CH:11]=[CH:12][N:13]([CH3:14])[C:7]3=[N:6][C:5]=2[CH3:15])[CH2:19][CH2:20]1
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: Cc1nc2n(C)ccn2c(=O)c1CCCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: Cc1nc2n(C)ccn2c(=O)c1CCN1CCC(Nc2nc3ccccc3[nH]2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A mixture of 11.3 parts of 6-(2-chloroethyl)-1,7-dimethylimidazo[1,2-a]pyrimidin-5(1H)-one (interm. 15), 18.9 parts of N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 16 parts of sodium carbonate, 0.01 parts of potassium iodide and 376 parts of N,N-dimethylacetamide was stirred overnight at 70° C. The reaction mixture was filtered and the filtrate was evaporated. The residue was taken up in a mixture of water, dichloromethane and methanol. The organic layer was separated and the aqueous layer was re-extracted with a mixture of dichloromethane and methanol. The combined organic layers were dried, filtered and evaporated. The residue was crystallized from ethanol, yielding 17.5 parts (86.3%) of 6-[2-[4-(1H-benzimidazol-2-ylamino)-1-piperidinyl]-ethyl]-1,7-dimethylimidazo[1,2-a]pyrimidin-5(1H)-one; mp. 229.5° C. (comp. 80).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N+:7]([O-])[CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:16][CH:15]=2)[C:4]1=[O:31])[CH3:2].[Cl-].[Cl-].[Ca+2].[C:35]([O:38]C(=O)C)(=[O:37])[CH3:36]>>[C:35]([O:38][CH2:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[N:5]([C:14]3[CH:15]=[CH:16][C:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:25]([CH3:26])[CH3:27])[CH:28]([CH3:30])[CH3:29])=[CH:18][CH:19]=3)[C:4](=[O:31])[N:3]([CH2:1][CH3:2])[C:11]=12)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2c1c(C)cc[n+]2[O-]
Agent: [Ca+2]
Agent: [Cl-]
Product: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(COC(C)=O)c21

Procedure:
The mixture of 1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (500 mg) in acetic anhydride (10 mL) was stirred at 80° C. under a dry atmosphere (CaCl2 tube) for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give [1-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methyl acetate (300 mg) as colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([CH2:8][N:9]2[CH2:37][CH2:36][C:12]3[NH:13][C:14]4[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH:23]5[CH2:28][CH2:27][N:26]([C:29](OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[O:21])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>Cl.O1CCOCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:37][CH2:36][C:12]3[NH:13][C:14]4[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH:23]5[CH2:24][CH2:25][N:26]([CH2:29][C:7]6[CH:38]=[CH:39][C:4]([C:1]#[N:2])=[CH:5][CH:6]=6)[CH2:27][CH2:28]5)=[O:21])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:38][CH:39]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(Cc2ccc(C(N)=O)cc2)CC4)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc4[nH]c5c(c4c3)CN(Cc3ccc(C(N)=O)cc3)CC5)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 182.9 %

Procedure:
A solution of tert-butyl 4-(2-(4-carbamoylbenzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (28, 745 mg, 1.4 mmol) in 4 N HCl/dioxane (20.0 mL) was allowed to stir at room temperature for 2 h. The reaction mixture was then concentrated to give a tan solid which was triturated with ethyl ether to give 2-(4-carbamoylbenzyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide as an off-white solid (700 mg, 99%); MS (ES) 432 (M+H).
Reaction SMILES: FC1C=C(OC)C=C(F)C=1[C:11]1=[C:12]([CH:42]=[CH:43][C:44]2[C:52]([CH3:54])([CH3:53])[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([S:55]([O-:58])(=[O:57])=[O:56])[CH:50]=3)[N+:45]=2[CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[CH2:13][CH2:14][CH2:15]/[C:16]/1=[CH:17]\[CH:18]=[C:19]1\[N:20]([CH2:34][CH2:35][CH2:36][CH2:37][S:38]([O-:41])(=[O:40])=[O:39])[C:21]2[C:26]([C:27]\1([CH3:29])[CH3:28])=[CH:25][C:24]([S:30]([O-:33])(=[O:32])=[O:31])=[CH:23][CH:22]=2.[Na+:67].[Na+].[Na+].B([C:73]1[C:74]([F:88])=[C:75]([C:83]([F:87])=[CH:84][C:85]=1[F:86])[O:76][CH2:77][CH2:78][CH2:79][C:80]([OH:82])=[O:81])(O)O>>[C:80]([CH2:79][CH2:78][CH2:77][O:76][C:75]1[C:74]([F:88])=[C:73]([C:11]2=[C:16]([CH:17]=[CH:18][C:19]3[C:27]([CH3:29])([CH3:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([S:30]([O-:33])(=[O:31])=[O:32])[CH:25]=4)[N+:20]=3[CH2:34][CH2:35][CH2:36][CH2:37][S:38]([O-:41])(=[O:40])=[O:39])[CH2:15][CH2:14][CH2:13]/[C:12]/2=[CH:42]\[CH:43]=[C:44]2\[N:45]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[C:46]3[C:51]([C:52]\2([CH3:54])[CH3:53])=[CH:50][C:49]([S:55]([O-:58])(=[O:56])=[O:57])=[CH:48][CH:47]=3)[C:85]([F:86])=[CH:84][C:83]=1[F:87])([OH:82])=[O:81].[Na+:67].[Na+:67].[Na+:67]
Reactant: O=C(O)CCCOc1c(F)cc(F)c(B(O)O)c1F
Reactant: COc1cc(F)c(C2=C(C=CC3=[N+](CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC/C2=C\C=C2\N(CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c(F)c1
Agent: CC1(C)C(/C=C/C2=C(c3c(F)cc(F)c(OCCCC(=O)O)c3F)/C(=C/C=C3/N(CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Agent: COc1cc(F)c(C2=C(/C=C/C3=[N+](CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC/C2=C\C=C2\N(CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c(F)c1
Agent: [Na+]
Product: CC1(C)C(C=CC2=C(c3c(F)cc(F)c(OCCCC(=O)O)c3F)/C(=C/C=C3/N(CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 38 was prepared analogously to compound 17 (Example 17), except with 4-(3-borono-2,4,6-trifluorophenoxy)butanoic acid as a starting material.
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[N:12][N:13]=[C:14]2[CH2:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29])C1C=CC=CC=1.[ClH:30]>C(O)(=O)C.C1(C)C=CC=CC=1>[ClH:28].[ClH:30].[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[CH2:21][C:14]1[C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[C:10]=2[CH:11]=[N:12][N:13]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
5-Benzyloxy-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (4.3 g, 10.08 mmoles), prepared as described in example 71, in glacial acetic acid and 7% HCl was put in a flask under stirring at room temperature for ½ hour, then at 60° C. for 1 hour. The mixture was brought to dryness, taken up more times in toluene to give a solid which was triturated in acetone and dried to give 4.04 g of the title compound (yield: 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=1.[C:17]1([C@@H:23]([CH3:26])[CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:25][CH2:24][C@@H:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:26])[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Reactant: C[C@@H](CN)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCCCNC[C@H](C)c2ccccc2)c1
Reaction time: 120 h
Yield: 74.6 %

Procedure:
[3-(3-Bromo-propoxy)-phenyl]-acetic acid methyl ester (11.48 g, 0.04 mole) in acetonitrile (300 mL) was added dropwise over 45 minutes to a mixture of (R)-2-Phenyl-propylamine (1.3 eq., 7.04 g, 0.052 mole), sodium iodide (18.0 g, 0.12 mole), and potassium carbonate (16.6 g, 0.12 mole) in acetonitrile (2000 mL). The mixture was stirred five days. The reaction mixture was filtered and the filter cake washed with acetonitrile (500 mL). The acetonitrile was evaporated and the residue dissolved in methylene chloride and washed with water(2×), dried over magnesium sulfate, filtered and evaporated. The resulting residue was purified by silica gel chromatography (using 3% to 10% methanol/methylene chloride as elutant) to give the title compound (10.19 g, 75%). MS (ESI) 342 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH3:2].[Cl:12][CH:13]=[CH:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Cl:12]/[CH:13]=[CH:14]/[CH2:15][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:1][CH3:2]
Reactant: ClC=CCCl
Reactant: CCNCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C/C=C/Cl)Cc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 4.28 g (20 mmol) of N-ethyl-3-bromobenzylamine in 30 ml of N,N-dimethylformamide were added 2.44 g (22 mmol) of 1,3-dichloropropene and 1.70 g (12 mmol) of ground potassium carbonate under ice cooling. The mixture was stirred for 8 hours at 60° C., poured into 40 mi of ethyl acetate, washed with 40 ml×2 of water and 40 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 3.70 g (yield: 64%) o -f the above identified compound as an oil.