Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=2)[CH:7]=1)=[O:4].[CH3:26][NH:27][CH3:28]>CN(C)C(=O)C>[CH3:26][N:27]([CH3:28])[CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=2)[CH:7]=1)=[O:4]
Reactant: CNC
Reactant: CNc1nccc(-c2cc(NC(=O)CCl)c3cc(OC)ccc3c2)n1
Solvent: CC(=O)N(C)C
Product: CNc1nccc(-c2cc(NC(=O)CN(C)C)c3cc(OC)ccc3c2)n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-N-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)acetamide 34 (0.125 mg, 0.35 mmol) in N,N-dimethylacetamide (1 mL), dimethylamine (1.5 mL, 2M solution in methanol, 3 mmol) was added. The reaction mixture was stirred at 60° C. overnight. The crude reaction mixture was concentrated under high vacuum and which was purified by reverse phase chromatography on preparative LC/UV/MS system using a mass triggered fractionation. Compound was eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 mL/min with acetonitrile/water gradient using 0.1% FA as a modifier. 2-(dimethylamino)-N-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)acetamide 137 was isolated as a yellow-orange solid (0.050 g). M.p.=70-73° C. 400 MHz 1H NMR (DMSO-d6) δ: 9.96 (s, 1H), 8.49 (s, 1H), 8.38 (s, 2H), 8.01 (d, J=8.6 Hz, 1H), 7.29-7.14 (m, 4H), 3.92 (s, 3H), 3.24 (s, 2H), 2.90 (br s, 3H), 2.42 (s, 6H); Experimental Elemental Analysis (0.13 equivalents of water)=65.32% C, 6.36% H, 18.75% N; Calculated Elemental Analysis 65.32% C, 6.37% H, 19.04% N; LCMS (m/z): 367 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:25]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1)[CH2:26][CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][C:34]([C@H:31]4[CH2:32][CH2:33][C@H:28]([CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30]4)=[O:35])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(O)cc3)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(OC(=O)[C@H]4CC[C@H](CCC)CC4)cc3)cc2)CC1
Reaction time: 72 h

Procedure:
0.40 g of 4-hydroxy-4'-(trans-4-pentylcyclohexyl)biphenyl, 0.21 g of trans-4-propylcyclohexanecarboxylic acid and 0.025 g of (4-dimethylamino)pyridine were dissolved in 25 ml of dichloromethane and then 0.31 g of N,N'-dicyclohexylcarbodiimide was added portionwise within 10 minutes while stirring. The mixture was left to stand at room temperature for 3 days and then the precipitate was filtered off. The filtrate was diluted with dichloromethane, washed twice with 20 ml of saturated sodium bicarbonate solution each time and then with water, dried over sodium sulphate and concentrated. The crude trans-4-propylcyclohexanecarboxylic acid 4'-(trans-4-pentylcyclohexyl)-4-biphenylyl ester obtained was chromatographed on silica gel with hexane/dioxane (volume ratio 19:1). The fractions which were pure according to thin-layer chromatography were pooled and recrystallized from ethyl acetate. Yield 0.33 g; m.p. (C-S) 92° C., cl.p. (N-I) 319° C.; further phase transitions: S-S 154° C., S-S 218.5° C., S-N 240° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[CH:14]=O.N1CCCCC1.C(O)(=O)C>CC(O)C>[CH3:1][O:2][C:3](=[O:9])[C:4]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:14][C:13]1[CH:12]=[C:11]([Cl:10])[CH:18]=[C:17]([Cl:19])[CH:16]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CCC(=O)CC(=O)OC
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.00 g (7.68 mmol) of 3-oxovaleric acid methylester and 1.34 g (7.68 mmol) of 3,5-dichlorobenzaldehyde were dissolved in 20 ml of 2-propanol. 65.4 mg (0.768 mmol) of piperidine and 46.1 mg (0.768 mmol) of acetic acid were added and stirred at room temperature for one day. After the solvent was evaporated under reduced pressure, ethyl acetate was added thereto. The reaction mixture was washed with 1 N hydrochloric acid and then with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:7]=2.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>ClCCl>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([OH:13])=[C:3]([NH:2][C:29](=[O:32])[CH2:30][CH3:31])[CH:4]=[N:5]2)=[CH:10][CH:9]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1O
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cnc2cc(OCc3ccccc3)ccc2c1O
Yield: 96.5 %

Procedure:
To a stirred solution of 3-amino-7-benzyloxyquinolin-4-ol hydrochloride (40.4 g, 133.4 mmol), and triethylamine (2.5 eq., 33.8 g, 333.6 mmol) in dichloromethane (1000 mL) at room temperature, was slowly added propionyl chloride (1.1 eq., 13.6 g, 146.8 mmol). After 6 hours the reaction was quenched with water (250 ml). The reaction mixture was transferred to a separatory funnel and the layers were separated. The dichloromethane layer was concentrated to provide 41.5 g of N-(7-benzyloxy-4-hydroxyquinolin-3-yl)propionamide as a pale tan crystalline solid. MS (ACPI) m/z=323 (M+H)+. This material was carried on without further purification to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:26]=2)=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([F:35])([F:34])[F:23])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2C(F)(F)F)c1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1cccc(C(F)(F)F)c1
Yield: 146.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.057 g (72%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-(trifluoromethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:49]=[C:50](Cl)[O:51][C:52](Cl)(Cl)Cl.[O:57]1[CH2:62][CH2:61]C(O)[CH2:59][CH2:58]1>C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:50](=[O:49])[O:51][CH:52]7[CH2:61][CH2:62][O:57][CH2:58][CH2:59]7)[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: OC1CCOCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](NC(=O)OC5CCOCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 60 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (20 mg) is dissolved in toluene (2 mL), treated dropwise with a solution of diphosgene (3.4 μL) in toluene (1 mL) and stirred for 12 hours at 60° C. Tetrahydro-2H-pyran-4-ol (2.7 μL) is added and the mixture is heated for 12 hours at 60° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound. LC (method 5): tR=1.22 min.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:18]([Sn](=O)CCCC)CCC.C([C@@]1(O)[C@H](OCCCC)[C@@H](C(=[SnH2])O)O[C@H]1N1C=CC(=O)NC1=O)CCC.IC>>[CH3:18][O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12]
Reactant: CCCC[Sn](=O)CCCC
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CCCCO[C@@H]1[C@@H](C(O)=[SnH2])O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]1(O)CCCC
Solvent: CI
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
As per the procedure of Example 49, uridine (8.5 g) was treated with dibutyl tin oxide (8.2 g, 1 eq). The resulting 2',3'-O-dibutylstannylene uridine was treated with iodomethane (16 ml) at 42° C. as per Example 50 to give a mixture of the 2' and 3' alkylated products (3.5 g) as a foam.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[C:31]#[CH:32]>CN(C)C=O.O>[C:31]1([C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH:32]=[N:14][N:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][CH2:23][C:17]=3[C:16]=12
Reactant: C#CC(=O)OCC
Reactant: N[n+]1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.9 %

Procedure:
To a mixture of 5-amino-2,3-dihydrofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (8.00 g, 25.0 mmol) and potassium carbonate (4.84 g, 35.0 mmol) in dimethylformamide (100 mL) was added ethyl propiolate (2.80 mL, 27.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (980 mg, yield 17%).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].O>O1CCCC1.C(OCC)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([CH:23]=[O:24])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(COc2ccccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(COc2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-bromo-benzyloxy)-pyridine described in Manufacturing Example 230-1-1 (34 g, 128 mmol) in tetrahydrofuran (120 mL) was added dropwise n-butyl lithium (50 mL, 2.6 M hexane solution, 134 mmol) at −78° C. After stirring for 30 minutes, N,N-dimethyl formamide (10 mL, 134 mmol) was added dropwise to this reaction solution at −78° C., which was stirred at room temperature. Water and ethyl acetate were added to the reaction solution, and liquid separation was carried out. The ethyl acetate layer was washed with water (twice) and sodium chloride water (once). The aqueous layers were combined and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water (twice) and aqueous sodium chloride (once). The previously obtained ethyl acetate layer and the ethyl acetate layer obtained this time were combined, dried over anhydrous magnesium sulfate, and then filtered. This filtrate was concentrated under a reduced pressure to obtain the title compound (26.8 g) as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].P(Br)(Br)[Br:15]>C(Cl)Cl.O.[Cl-].[Na+].O>[Br:15][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CBr)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 191.1 %

Procedure:
(4-methoxy-3-nitrophenyl)methanol (215 mg, 1.174 mmol) was dissolved, under N2 atmosphere, in dry DCM and cooled to 0° C. PBr3 (55.4 μl, 0.587 mmol) was added, and the reaction was stirred RT for 1 hour. Ice and DCM were added to the reaction mixture. The mixture was diluted with WATER and brine and extracted twice with DCM. The organic layers were dried and evaporated to dryness to give 4-(bromomethyl)-1-methoxy-2-nitrobenzene (276 mg, 1.122 mmol, 96% yield) that was used in the next step without further purification.
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])C(C)C.[CH2:17](Br)[C:18]#[CH:19].OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:15]([O:14][C:9](=[O:13])[C:6]([CH3:7])([CH3:8])[CH2:19][C:18]#[CH:17])[CH3:16]
Reactant: CCOC(=O)C(C)C
Reactant: CC(C)[N-]C(C)C
Reactant: C#CCBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Product: C#CCC(C)(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of 22.0 ml (2.0 M in THF/n-heptane/ethylbenzene, 44 mmol) LDA in 40 ml THF was treated during 10 min at −78° C. with 5.47 ml (40 mmol) ethyl isobutyrate in 4.7 ml THF. After 1 h at this temperature, a solution of 4.90 ml (80% by weight in toluene, 44 mmol) of propargyl bromide in 7.5 ml THF was added dropwise. The solution was naturally warmed to 0° C. and after 2 h treated carefully with aqueous 10% KHSO4 and extracted with ether (three times). The organic phases were washed with aqueous 10% KHSO4 and aqueous 10% NaCl solution. The organic phase was dried (Na2SO4) and evaporated to give 5.70 g of the title compound as volatile orange liquid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@@H:22]1[O:31][C@H:30]2[C@@H:25]([O:26][CH:27]([CH:32]=[CH2:33])[O:28][CH2:29]2)[C@H:24]([OH:34])[C@H:23]1[OH:35])[CH:2]=[CH2:3].C([BH3-])#N.[Na+].FC(F)(F)S(O)(=O)=O.O>O1CCCC1>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:23]([OH:35])[C@@H:24]([OH:34])[C@H:25]([OH:26])[C@@H:30]([CH2:29][O:28][CH2:27][CH:32]=[CH2:33])[O:31]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@@H]2COC(C=C)O[C@H]2[C@H](O)[C@H]1O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC[C@H]1O[C@@H](c2cc(Cc3ccc(OCC)cc3)c(Cl)cc2OCC=C)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
To a solution (4aR,6S,7R,8R,8aS)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-2-vinylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (14, 669 mg, 1.33 mmol) from Step 1 in tetrahydrofuran (13 mL) was added sodium cyanoborohydride (642 mg, 9.71 mmol), molecular sieves (407 mg) and was added cautiously trifluoromethanesulfonic acid. After addition, the mixture was stirred for another 0.5 h, before being poured into H2O. The aqueous phase was extracted with dichloromethane and the combined organic fractions were washed with brine. The organic layer was dried over magnesium sulfate and filtered through a pad of silica gel. The filtrate was evaporated and went to next step.
Reaction SMILES: [N:1]1[N:2]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[N:3]=[CH:4][CH:5]=1.O.NN.CO>CO.O1CCCC1>[N:1]1[N:2]([CH2:6][CH2:7][CH2:8][NH2:9])[N:3]=[CH:4][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCn1nccn1
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NCCCn1nccn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19.6 %

Procedure:
To a mixture solution of 2-(3-[1,2,3]triazol-2-yl-propyl)-isoindol-1,3-dione (1782 mg, 6.95 mmol) in methanol-tetrahydrofuran (5:4, 27 mL) was added hydrazine monohydrate (371 μl, 7.65 mmol), and the solution was stirred for 5 days at room temperature. Methanol (8 mL) was added thereto, followed by further stirring for 3.25 hours under reflux. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was dissolved in tetrahydrofuran, adsorbed onto NH silica gel, purified by NH silica gel chromatography (ethyl acetate-methanol), and the title compound (491 mg, 1.36 mmol, 19.6%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].C(=O)(O)[O-].[Na+].O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O>COCCOC.C(Cl)Cl.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>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:27]=3[O:26][CH3:25])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Reactant: COc1ccncc1B(O)O
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CCCNC(=O)c1nnc2c(-c3cnccc3OC)cccc2c1N
Yield: 60.2 %

Procedure:
To a stirred solution of 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (1.00 g, 2.81 mmol), sodium bicarbonate (473 mg, 5.62 mmol) and tetrakis(triphenylphosphine)palladium(0) (974 mg, 0.84 mmol) in 1,2-dimethoxyethane (180 mL)/water (30 mL) at 85° C. under nitrogen was added the aqueous solution of 4-methoxy-pyridine-3-boronic acid (25 mg/mL) dropwise, maintaining the internal temperature between 80° C. and 85° C. The reaction was monitored by HPLC until completed. Upon the completion, 2.42 equivalents of 4-methoxy-pyridine-3-boronic acid (1.16 g, 6.80 mmol) were applied. The reaction mixture was diluted with methylene chloride (300 mL), washed with water twice, dried through MgSO4, and then the solvent was evaporated. The residual was purified by flash chromatography using a gradient of methanol in methylene chloride to give a yellow solid. The yellow solid was crystallized from methylene chloride/methanol (2/1) to give an off-white needle crystal as the title compound (570 mg, 60.2% yield). 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=5.8 Hz, 1H), 8.53 (br, 1H), 5.11 (m, 6H), 8.46 (s, 1H), 7.94 (t, J=4.9 Hz, 1H), 7.74 (d, J=4.8 Hz, 2H), 6.96 (d, J=5.8 Hz, 1H), 3.78 (s, 3H), 3.45 (q, J=6.7 Hz, 2H), 1.66 (m, overlapped with H2O), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=338 (M+H) HPLC 1.28 min.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[F:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:14]=1[C:15](=[O:18])[CH2:16][Br:17]>C(#N)C>[BrH:17].[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:16][C:15]([C:14]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:13]=3[F:12])=[O:18])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: O=C(CBr)c1c(F)cccc1F
Solvent: CC#N
Product: Br
Product: Cc1nc2n(CC(=O)c3c(F)cccc3F)cccc-2c1C
Yield: 55.9 %

Procedure:
A solution of 100 mg (0.68 mmol) 2,3-dimethylpyrrolo[2,3-b]pyridine and 193 mg (0.82 mmol) 2,6-difluorophenacyl bromide in 2 ml acetonitrile were refluxed for 3 h. Working up in the same manner as described in example 17 gave 145 mg (54% ) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C@@H:11]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:30][CH2:29][C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[NH:26][C:25]3=[O:35])[CH2:20][CH2:19]2)=[O:17])[C:12]([OH:14])=O)[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[O:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[O:35]=[C:25]1[N:24]([CH:21]2[CH2:22][CH2:23][N:18]([C:16]([O-:17])=[O:36])[CH2:19][CH2:20]2)[CH2:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[NH:26]1.[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8])[CH2:10][C@@H:11]([NH-:15])[C:12](=[O:14])[N:45]1[CH2:44][CH2:43][N:42]([CH:39]2[CH2:40][CH2:41][O:36][CH2:37][CH2:38]2)[CH2:47][CH2:46]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1O
Product: Cc1cc(C[C@@H]([NH-])C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1O
Product: O=C([O-])N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
Prepared analogously to Example 7i from 70 mg (0.14 mmol) (R)-3-(3-chloro-4-hydroxy-5-methyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 27.4 mg (0.16 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [CH2:1]([N:8]1[C:12](Br)=[N:11][N:10]=[C:9]1[Br:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH2:1]([N:8]1[C:12]([O:16][CH3:15])=[N:11][N:10]=[C:9]1[Br:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1nnc(Br)n1Cc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nnc(Br)n1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4-benzyl-3,5-dibromo-4H-1,2,4-triazole (compound 91.2, 3.71 g, 11.7 mmol) in MeOH 15 mL) was added NaOMe (1.26 g, 23.4 mmol) and the mixture was refluxed for 18 hours. The mixture was cooled somewhat and additional NaOMe was added (1.26 g, 23.4 mmol). The mixture was refluxed for an additional 5 hours, then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with water (30 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to yield 3.13 g (theoretical) of the title compound as a clear oil. m/z (ES+) 269 (M+H)+.