Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:34][CH2:33][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[N:21]=[CH:22][C:17]=2[CH2:16]1)=O)(C)(C)C.C(N(CC)CC)C.[Br:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(Cl)Cl>[Br:42][C:43]1[CH:44]=[C:45]([S:49]([N:15]2[CH2:34][CH2:33][C:18]3[N:19]=[C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[N:21]=[CH:22][C:17]=3[CH2:16]2)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cccc(Cl)c3)ncc2C1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ncc2c(n1)CCN(S(=O)(=O)c1cccc(Br)c1)C2)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
Trifluoroacetic acid 6.2 ml (81 mmol) was added to a solution of 2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 487 mg (1.25 mmol) in CH2Cl2 (8 ml) under nitrogen as inert gas and stirring was performed for 1.5 h at RT. After removal of the solvent, the intermediate (3-chloro-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide trifluoroacetate) was dissolved in CH2Cl2 (15 ml). After the addition of triethylamine 820 μl (5.84 mmol), the solution was cooled to 0° C. and 3-bromo benzenesulfonyl chloride 311 mg (1.37 mmol) was added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at RT. After removal of the solvent, purification was performed by means of column chromatography and the product N-[6-(3-bromo-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-3-chloro-benzamide 525 mg (81% of theoretical) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17])[C:6](N1C=CN=C1)=[O:7].[C:21](=[N:24][OH:25])([NH2:23])[CH3:22]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]=1[O:16][CH3:17])[C:6]([O:25][N:24]=[C:21]([NH2:23])[CH3:22])=[O:7]
Reactant: COc1cc(C(=O)n2ccnc2)cc([N+](=O)[O-])c1OC
Reactant: CC(N)=NO
Solvent: CN(C)C=O
Product: COc1cc(C(=O)ON=C(C)N)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10.0 g of 1-(3,4-dimethoxy-5-nitrobenzoyl)imidazole in 50 ml of-dimethylformamide are treated with 6.95 g of acetamidoxime, whereupon the mixture is stirred at 70° for 1 hour. After cooling, the mixture is poured into 500 ml of ice-water and stirred for 30 minutes. The separated crystals are filtered under suction and washed with water. After crystallization from ethyl acetate there is obtained N'-[(3,4-dimethoxy-5-nitrobenzoyl)oxy]acetamidine in the form of colorless crystals of m.p. 165°-166°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.C([Li])CCC.CCCCCC.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C>O1CCCC1>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([B:32]([OH:37])[OH:33])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(Br)ccc1NC(=O)CCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(B(O)O)ccc1NC(=O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 23.3 %

Procedure:
A solution of N1-(4-bromo-2-methoxyphenyl)-3-phenylpropanamide (1.004 g, 3 mmol) in anhydrous tetrahydrofuran (30 mL) at −78° C. was treated with a solution of 1.6 M n-butyl lithium in hexane (4.7 mL, 7.5 mmol). The reaction mixture was stirred at −78° C. for 40 min. Tri-isopropyl borate(1.05 mL, 4.5 mmol) was added to this reaction mixture, and stirred at −78° C. for 20 min. The acetone/dry ice bath was removed. The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with 2.5 N hydrochloric acid solution (30 mL). The organic layer was removed under reduced pressure. Ethyl acetate was added to the acidic aqueous layer. The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel, using 1:1 dichloromethane:ethyl acetate as eluent. The gradient was changed to 15% methanol in dichloromethane to remove the baseline product to give 0.209 g (23%) of 3-methoxy-4-[(3-phenylpropanoyl)amino]phenylboronic acid. 1H NMR (DMSO-d6, 400 MHz) δ 9.08 (s, 1H), 7.89-7.95 (m, 3H), 7.45-7.42 (s, 1H), 7.35-7.16 (m, 5H), 3.82 (s, 3H), 2.91-2.81 (m, 2H), 2.74-2.70 (s, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.389 min (95%).
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([OH:19])[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.[Cl:20][C:21]1[CH:30]=[C:29]([CH2:31]Cl)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCCC1>[Cl:20][C:21]1[CH:30]=[C:29]([CH2:31][O:19][CH:12]([C:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=2[Cl:4])[CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: ClCc1cc(Cl)nc2ccccc12
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(C(Cn2ccnc2)OCc2cc(Cl)nc3ccccc23)c(Cl)c1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
In a three necked flask, fitted with stirrer, reflux condenser and gas inlet tube are introduced 30 g of sodium hydroxide (0.75 mol) and 30 ml of water. While passing nitrogen through the flask, the solution is cooled to 45° C. and then are added 7.7 g of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (0.03 mol), 0.5 g of benzyltrimethylammonium chloride, 100 ml of tetrahydrofuran and 6.4 g of 2-chloro-4-chloromethylquinoline (0.03 mol). Then the mixture is stirred vigorously for 1.5 hours at 60°-65° C. After cooling the mixture is separated, and the lower aqueous sodium hydroxide is extracted with 20 ml of tetrahydrofuran. The combined tetrahydrofuran layers are dried with sodium sulfate, charcoaled, filtered and after the solvent has been removed, the residual oil is extracted with 175 ml of ether, and the etheral solution is allowed to stand overnight in a refrigerator. The crystallized 2-chloro-4-[[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy]methyl]quinoline is recrystallized from ethyl acetate (refrigerator). Yield 5.5 g (42.3%); m.p. 180°-181° C.
Reaction SMILES: C([N:8]1[C:20]2[C:19]([OH:21])=[C:18]3[N:22](C(OC(C)(C)C)=O)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:37])[CH:13]=2)(OC(C)(C)C)=O.Cl.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]Cl.C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O>CC(C)=O>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:18]1[C:19]([O:21][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[C:20]3[NH:8][C:9]4[CH:10]=[CH:11][C:12]([F:37])=[CH:13][C:14]=4[C:15]3=[CH:16][C:17]2=1
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Temperature: 25 °C
Yield: 64.5 %

Procedure:
A mixture of 5,7-diBOC-2,10-difluoro-6-hydroxyindolo[2,3-b]carbazole (406.8 mg, 0.8 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (126.8 mg, 0.88 mmol) and K2CO3 (10 equivalents) in 4A-molecular-sieve-dried acetone (40 mL) was magnetically stirred and heated to reflux under Ar. After the reaction was complete, it was cooled to room temperature. The inorganic salt was removed by filtration and washed with a small quantity of acetone. The combined acetone solution was concentrated on a rotavapor and dried under vacuum pump. The crude product was purified by flash chromatography. The resultant product 2-(2,10-difluoro-5,7-diBOC-indolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine was dissolved in CH2Cl2 (40 mL), and trifluoroacetic acid (˜40 equivalents) was added. The reaction was stirred at room temperature overnight, concentrated, and dried under vacuum pump. The crude compound was dissolved in ethyl acetate (40 mL), washed with saturated NaHCO3 solution, dried under Na2SO4, concentrated, and flash chromatography to provide the desired product 2-(2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (195.9 mg, 65%). 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.40 (s, 2 H), 8.56 (s, 1 H), 7.87 (dd, J=9.2, 2.4 Hz, 2 H), 7.44 (dd, J=8.4, 4.4 Hz, 2 H), 7.20-7.11 (m, 2 H), 4.30 (t, J=5.8 Hz, 2 H), 2.72 (t, J=5.8 Hz, 2 H), 2.32 (s, 6 H); MS (ESI) m/z 378.1 (M−H)−; MS (ESI) m/z 380.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]([N:20]([CH:34]1[CH2:36][CH2:35]1)[C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[C:6]([C:8]1[N:9]=[N:10][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)=O)[CH3:2].FC(F)(F)C([O-])=O.[NH4+:45]>>[CH2:1]([O:3][C:4]([C:5]1[N:20]([CH:34]2[CH2:35][CH2:36]2)[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=2)=[N:45][C:6]=1[C:8]1[N:9]=[N:10][N:11]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=1)=[O:37])[CH3:2]
Reactant: CCOC(=O)C(C(=O)c1cn(Cc2ccccc2)nn1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Product: CCOC(=O)c1c(-c2cn(Cc3ccccc3)nn2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1

Procedure:
The title compound was prepared from 3-(1-benzyl-1H-[1,2,3]triazol-4-yl)-2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-propionic acid ethyl ester in direct analogy to intermediate 8B, by reaction with ammonium trifluoroacetate. MS: 498.1 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[N:26]4[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)=[C:20]([C:28]4[CH:29]=[CH:30][C:31]5[C:35]([CH:36]=4)=[N:34][N:33]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:32]=5)[CH:19]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([N:33]1[CH:32]=[C:31]2[C:35]([CH:36]=[C:28]([C:20]3[CH:19]=[C:18]([C:12]4[CH:11]=[C:10]5[C:15]([CH2:16][CH2:17][NH:8][CH2:9]5)=[CH:14][CH:13]=4)[N:26]4[C:21]=3[C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)[CH:29]=[CH:30]2)=[N:34]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(-c3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-[4-amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.7 g, 4.7 mmol) in DCM (17 mL) was added TFA (8.6 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and ethyl acetate was added. Saturated, aqueous NaHCO3 was added until the pH was basic. Yellow gum formed in the wall of glass, it was dried in vacuum oven overnight and the title product was obtained as light yellow solid, 2.2 g (98%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.1 (m, 2 H), 3.2 (m, 2 H), 2.80 (m, 2 H); ES-MS m/z 472.29 [M+H]+, HPLC RT (min) 2.22.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH3:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CC(C)COC(Cl)=O.[BH4-].[Na+].Cl>C1COCC1.O.CCOC(C)=O>[OH:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:13][O:14][CH3:15]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 58.8 %

Procedure:
To a mixture of (S)-2-(tert-butoxycarbonylamino)-3-methoxypropanoic acid (10.9 g) and N-methylmorpholine (5.6 g, 55 mmol) in THF (50 mL) was added 2-methylpropylchloroformate (7.48 g, 55 mmol) in THF at −15° C. The reaction mixture was stirred −15° C. for 15 min, after which NaBH4 (6.0 g, 159 mmol) in water (10 mL) was added. The reaction mixture was stirred for 30 min, then diluted with EtOAc, and neutralized with dilute HCl. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc and petroleum ether (EtOAc/PE=1.5/1) to give the title compound (6.0 g, 58%). 1H NMR (400 MHz, CDCl3) δ ppm 5.23 (s, 1H), 3.80 (d, J=8.0 Hz, 2H), 3.72-3.68 (m, 1H), 3.60-3.52 (m, 2H), 3.38 (s, 3H), 2.85 (s, 1H), 1.47 (s, 9H).
Reaction SMILES: [Na+].[Na+].P(O[CH2:8][C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)([O-])([O-])=O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4[O:48][C@@H:47]([N:49]5[CH:54]=[C:53]([C:55]([NH2:57])=[O:56])[CH2:52][CH:51]=[CH:50]5)[C@H:46](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.CCOCCOCCO>C(O)C(N)(CO)CO.Cl>[C:47]([NH:49][C:50]1[CH:51]=[CH:52][C:53]([C:55]([NH2:57])=[O:56])=[CH:54][CH:8]=1)(=[O:48])[CH3:46]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)([O-])[O-]
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Na+]
Solvent: CCOCCOCCO
Product: CC(=O)Nc1ccc(C(N)=O)cc1

Procedure:
The following components were combined at a temperature between 0°-4°: G6PDH, 10.0 ml of ca. 2 mg/ml solution suspended in 0.055 M Tris-HCl buffer; Glucose-6-phosphate disodium salt, 100 mg; NADH, 200 mg; Carbitol, 3.0 ml.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([CH2:15][OH:16])[CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CCCCC.C1COCC1.C(OCC)(=O)C>[CH2:3]([O:10][CH2:11][CH:12]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(CO)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
NaH (0.87 g, 80% dispersion in oil, 29.1 mmol) was washed three times with dry pentane, dried in vacuo, and then suspended in 60 mL of dry THF. A solution of 2-benzyloxymethyl-1,3-propanediol (5.70 g, 29.1 mmol) in 5 mL of THF was next added dropwise over 20 min. and the reaction mixture stirred at room temperature for 1.5 hrs. to give a white slurry. t-Butyldimethylsilylchloride (4.38 g, 29.1 mmol) was then added portionwise over 3 min. and the reaction mixture stirred at room temperature for 2 hours further. The mixture was next diluted with 150 mL of ethyl acetate and washed with 10% aqueous potassium carbonate and brine, dried over MgSO4, filtered, and concentrated to give a colorless oil. Purification by column chromatography on silica gel (ethyl acetate/hexanes) provided 7.41 g (82%) of 2-benzyloxymethyl-3-t-butyldimethylsiloxy-1-propanol as a clear, colorless liquid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:48][CH:49]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:50]1[CH:51]=[CH:52][C:53]([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])=[N:54][CH:55]=1>C(OCC)(=O)C>[OH:1][C:2]1[C:7]([C:8]([NH:48][CH:49]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:50]2[CH:51]=[CH:52][C:53]([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])=[N:54][CH:55]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Reactant: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid, 1-1-h, (1 g, 4.6 mmol) in ethyl acetate (20 ml) was added HATU (1.75 g, 4.6 mmol), Et3N (465 mg, 4.6 mmol) and diethyl {5-[amino(phenyl)methyl]pyridin-2-yl}phosphonate (4-g) (1.47 g, 4.6 mmol). The resulting mixture was stirred at room temperature for 2 hour. Then it was filtered before diluted with saturated NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography to provide the product, 4-1, (360 mg, 15%). 1H NMR (CD3OD, 300 MHz,): δ 10.56 (m, 1H), 8.66 (m, 3H), 8.37 (m, 1H), 7.83 (m, 3H), 7.52 (m, 1H), 7.23 (m, 5H), 6.33 (m, 1H), 4.09 (m, 4H), 1.30 (m, 6H).
Reaction SMILES: [C:1](Cl)(=[O:14])[O:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[NH:16]1[CH2:21][CH:20]=[CH:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C1COCC1.O>[N:16]1([C:1]([O:2][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)=[O:14])[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17]1
Reactant: O=C(Cl)OCc1ccc2ccccc2c1
Reactant: C1=CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccc2ccccc2c1)N1CC=CCC1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
Naphthalen-2-ylmethyl carbonochloridate (11.00 g, 49.85 mmol) was dissolved in THF (25 mL) and this was added dropwise to a cooled (0° C.) solution of 1,2,3,6-tetrahydropyridine (3.79 ml, 41.5 mmol) and NaHCO3 (4.18 g, 49.8 mmol) in water (88 mL). A precipitate formed in the reaction immediately, therefore after the addition, additional THF (63 mL) was added to solubilize the reaction mixture. The solution was removed from the bath and warmed to ambient temperature for 16 hours. The reaction was concentrated in vacuo then methylene chloride was added. The mixture was separated, the aqueous layer was washed with methylene chloride, and the combined organics were dried over Na2SO4 and concentrated in vacuo to provide the desired product as an oil (11 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[S:12][C:13]([CH3:16])=[N:14][N:15]=2)[C:3]=1I.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N.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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([C:29]#[N:30])=[C:4]([NH:9][CH2:10][C:11]2[S:12][C:13]([CH3:16])=[N:14][N:15]=2)[N:5]=1
Reactant: Cc1nnc(CNc2nc(N)nc(Cl)c2I)s1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nnc(CNc2nc(N)nc(Cl)c2C#N)s1
Temperature: 120 °C
Yield: 43 %

Procedure:
To a stirred solution of 16-2 (639 mg, 1.67 mmol), and zinc cyanide (98 mg, 0.84 mmol) in DMF (6 mL) under nitrogen was added Pd2(dba)3 (76 mg, 0.08 mmol) and DPPF (93 mg, 0.17 mmol) and the resulting mixture was heated to 120° C. for 90 minutes. The reaction was allowed to cool and partititioned between ethyl acetate and a saturated sodium bicarbonate solution. The organic phase was concentrated and flash column separation using a 10-100% ethyl acetate/hexane gradient gave 16-3 as a solid (200 mg, 43%). MS (ES) (M+H)+: observed=282.2, calculated=282.7.
Reaction SMILES: C(Cl)Cl.[NH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1.[Br:16][CH2:17][C:18](Br)=[O:19].[Cl-].[NH4+]>C(N(CC)CC)C>[Br:16][CH2:17][C:18]([NH:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:19]
Reactant: O=C(Br)CBr
Reactant: NC1CCCOc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)NC1CCCOc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a 5 ml methylene chloride solution of 150 mg of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine (Japanese Unexamined Patent Publication (Kokai) No. 4-178381) and 0.15 ml of triethylamine was added dropwise, under ice cooling, 0.08 ml of bromoacetyl bromide. This was then stirred at room temperature for 1 hour. To the reaction was added 5 ml of a saturated aqueous solution of ammonium chloride, then extraction was performed with methylene chloride. The extract was washed with saturated saline, dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=25:1) to obtain the above-referenced compound (8) in an amount of 165 mg (yield of 65%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6](Br)[C:5]=1[OH:12])([O-:3])=[O:2].[CH2:13]([N:15](CC)CC)C.CN(C1C=CC=CN=1)C.[Cu]C#N>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:13]#[N:15])[C:5]=1[OH:12])([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1Br
Agent: N#C[Cu]
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(O)c1C#N
Temperature: 80 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
2-Nitro-5-methyl-6-bromophenol (100 mg, 0.433 mmol) was dissolved in dimethyl formamide (2 mL) followed by the addition of triethylamine (0.175 g, 1.73 mmol). The addition of a catalytic amount dimethylamino pyridine was then made, followed by addition of copper (I) cyanide (155 mg, 1.73 mmol). The mixture was allowed to stir at 80° C. for 4 hours. The solvent was evaporated and chromatography of the resulting solid on silica gel (2% MeOH/CH2Cl2) gave the desired product (70 mg, 91%). 1H NMR (CD3COCD3): δ 8.30 (d, 1H), 7.15 (d, 1H), 2.61 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[CH2:15]3)=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:28][C:29]1([CH2:34][OH:35])[CH2:33][CH2:32][NH:31][CH2:30]1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[OH:35][CH2:34][C:29]1([CH3:28])[CH2:33][CH2:32][N:31]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:16]3[CH2:15][N:14]([C:12]([C:10]4[O:11][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[N:8][N:9]=4)=[O:13])[CH2:17]3)=[CH:26][CH:25]=2)[CH2:30]1
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Reactant: CC1(CO)CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CO)CCN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Intermediate 71A (0.15 g, 0.43 mmol), intermediate 84A (0.098 g, 0.64 mmol) and TEA (0.238 mL, 1.72 mmol) were mixed in dichloromethane (4 mL). The mixture was stirred at RT for 30 min and then sodium triacetoxyhydroborate (0.182 g, 0.86 mmol) was added and the mixture was stirred at RT overnight. Aqueous NaHCO3 (sat., 4 mL) and dichloromethane (4 mL) were added and the mixture was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by preparative reverse-phase HPLC at pH 10 to give 21 mg (11%). 1H NMR (600 MHz, DMSO) δ 1.00 (s, 3H), 1.3-1.39 (m, 1H), 1.57-1.64 (m, 1H), 2.05 (d, 1H), 2.41-2.48 (m, 2H), 3.14-3.24 (m, 2H), 3.43-3.51 (m, 2H), 4.07-4.14 (m, 1H), 4.54-4.73 (m, 3H), 5.07-5.19 (m, 2H), 6.85 (d, 2H), 7.25 (d, 2H), 7.63-7.73 (m, 3H), 8.09 (d, 2H), LC purity: 94%.