Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]2[C:6]3=[C:7]([C@:13]([CH3:22])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][CH2:15][N:5]3[CH2:4][CH2:3]1)[CH:8]=[C:9]([NH2:12])[CH:10]=2.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>ClCCl>[CH3:1][C@:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]2[C:6]3=[C:7]([C@:13]([CH3:22])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][CH2:15][N:5]3[CH2:4][CH2:3]1)[CH:8]=[C:9]([NH:12][C:32]([NH:31][CH2:29][CH3:30])=[O:33])[CH:10]=2
Reactant: CCN=C=O
Reactant: C[C@@]1(c2ccccc2)CCN2CC[C@@](C)(c3ccccc3)c3cc(N)cc1c32
Solvent: ClCCl
Product: CCNC(=O)Nc1cc2c3c(c1)[C@](C)(c1ccccc1)CCN3CC[C@@]2(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (1S,7S)-1,7-dimethyl-9-amino-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline (9), (110 mg, 0.30 mmol) in dicloromethane (15 mL) was added ethyl isocyanate (0.026 mL, 0.328 mmol), mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The solvent was removed under reduced pressure and purified by MPLC) using silica gel column with 15 to 20% EtOAc:Hexane to get 1-((1S,7S)-1,7-dimethyl-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)-3-ethylurea (249), (96 mg 73%). 1H NMR (300 MHz, Acetone-d6) δ ppm 1.00 (t, J=7.18 Hz, 3H) 1.71 (s, 6H) 1.91-2.02 (m, 2H) 2.15-2.31 (m, 2H) 2.75-2.87 (m, 2H) 2.90-3.03 (m, 2H) 3.03-3.16 (m, 2H) 6.98 (s, 2H) 7.09-7.31 (m, 10H)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].[Li]CCCC.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[N:28]=[CH:27]2.[Na]>C1COCC1.[Cl-].[NH4+]>[F:15][C:2]([F:1])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[N:28]=[CH:27]2)[OH:4]
Reactant: Brc1ccc2c(cnn2-c2cccnc2)c1
Reactant: O=C(c1c[nH]c2ccccc12)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc2c(cnn2-c2cccnc2)c1)(c1c[nH]c2ccccc12)C(F)(F)F
Reaction time: 0.02 h
Yield: 9.8 %

Procedure:
To a chilled (−78° C.) solution of 241 mg (1.13 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-yl)ethanone in 5 mL of anhydrous THF was added 45 mg (1.13 mmol) of 60% NaH in mineral oil. In another flask, 452 μL (1.13 mmol) of n-BuLi was then added to a chilled (−78° C.) solution of 310 mg (1.13 mmol) of 5-bromo-1-pyridin-3-yl-1H-indazole in 10 mL of THF. After 1 minute, the sodium salt of 2,2,2-trifluoro-1-(1H-indol-3-yl)ethanone was added to the indazole anion via a cannula. After 1 hour, the mixture was diluted with 25 mL of saturated aqueous ammonium chloride and extracted with three 15 mL portions of ethyl acetate. The combined organic layers were washed with three 10 mL portions of brine, dried over magnesium sulfate, filtered and concentrated. The crude material was purified using Combiflash chromatography using EtOAc-hexanes (0-70% gradient) to afford 45 mg (10%) of 2,2,2-trifluoro-1-(1H-indol-3-yl)-1-(1-pyridin-3-yl-1H-indazol-5-yl)ethanol as a colorless solid.
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1)([O-:5])=[O:4].[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([Cl:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:21][C:22]1[N:27]=[C:26]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][CH2:9][C:8]3[CH:18]=[CH:19][CH:20]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=3)[CH:12]=2)[C:25]([Cl:29])=[CH:24][N:23]=1
Reactant: Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(CNc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 128.1 %

Procedure:
To a solution of N-(3-nitrobenzyl)benzene-1,3-diamine dihydrochloride (6.58 g, 0.021 mol) and 2,4,5-trichloropyrimidine (2.38 mL, 0.021 mol) in N,N-dimethylformamide (70 mL) was added potassium carbonate (10.1 g, 0.073 mol). The resultant mixture was stirred for 60 h at room temperature. The reaction mixture was filtered first to remove K2CO3, and then quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue (10.5 g), which was purified by silica gel column chromatography to give the desired product as a light yellow powder (6.19 g, 76%). LCMS for C17H14Cl2N5O2 (M+H)+: m/z=389.9.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[OH-].[Na+].Cl>CO>[C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH:13]([C:17]([OH:19])=[O:18])[CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1=Cc2cc(-c3ccccc3)ccc2CC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C(O)C1CCc2ccc(-c3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.2 %

Procedure:
To 7-phenyl-3,4-dihydronaphthalene-2-carboxylic acid (1.00 g) dissolved in methanol (25 ml) was added a concentrated sulfuric acid (0.1 ml), and the resulting mixture was heated at reflux for 48 hours. After cooling to room temperature, the reaction mixture was mixed with a 5% aqueous solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was then evaporated under reduced pressure to remove the solvent. To the resulting residue dissolved in ethanol (50 ml) was added dried 10% palladium on charcoal (0.05 g), and the resulting mixture was stirred at an ordinary temperature and under an atmospheric pressure for 48 hours. The palladium on charcoal was removed by a filtration operation, the filtrate was concentrated and the residue was then subjected to purification using column chromatography (ethyl acetate/hexane=1/2) to obtain an oily material. To this material dissolved in methanol (15 ml) was added a 1 N aqueous solution of sodium hydroxide (10 ml), and the resulting mixture was heated at reflux for 3 hours. After cooling to room temperature, the reaction mixture was acidified by the addition of a diluted hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate/hexane to obtain 7-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (677 mg) as colorless crystals.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[C:13]([F:21])=[CH:12][N:11]=1.C(N(CC)CC)C>ClCCl.CN(C1C=CC=CN=1)C>[Si:1]([O:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]1[C:13]([F:21])=[CH:12][N:11]=[C:10]([Cl:9])[N:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OCCCNc1nc(Cl)ncc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of t-butyldimethylsilyl chloride (1.63 g, 10.70 mmol) in dichloromethane (48.63 mL) was added 3-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-1-propanol (Example 80, 2.0 g, 9.73 mmol), followed by triethylamine (1.49 mL, 10.70 mmol) and dimethylaminopyridine (0.02 g, 0.19 mmol). The resulting cloudy mixture was stirred at rt for 18 h and then diluted with dichloromethane (80 mL). The mixture was washed with water (50 mL), dried over magnesium sulfate, and concentrated. The product was purified by column chromatography (67% hexanes in EtOAc) to give the title compound as a white solid (2.68 g, 86%). 1H NMR (300 MHz, CD2Cl2) δ 7.78 (d, 1H), 3.64-3.59 (m, 2H), 3.44-3.41(m, 2H), 1.82-1.73 (m, 2H), 0.84 (s, 9H), 0.001 (s, 6H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl.ClCCl.CN(C=O)C>[NH2:8][C@H:9]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH:10]([OH:14])[C:11]([NH:31][O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@H](CC1CCCCC1)C(O)C(=O)NOCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of Example 1C (0.20 g, 0.66 mmol), O-benzyl hydroxylamine hydrochloride (0.22 g, 1.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.17 g, 0.89 mmol), 1-hydroxybenzotriazole (0.14 g, 1.0 mmol), and N-methylmorpholine (0.40 mL, 3.6 mmol) in 5:1 dichloromethane/DMF (6 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with aqueous NaHCO3, brine, 10% KHSO4, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98:2/dichloromethane:methanol, and the purified concentrate was dissolved in saturated HCl/dioxane (8 mL), stirred for 1 hour, concentrated, treated with diethyl ether, then concentrated to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:7]=[C:8]([NH:10]C(OCC2C=CC=CC=2)=O)[CH:9]=1)=[O:4].CO>[Pd].O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(NC(=O)OCc2ccccc2)nn1Cc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)nn1Cc1ccc(OC)cc1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
In a round bottom flask, 5-benzyloxycarbonylamino-2-(4-methoxy-benzyl)-2H-pyrazole-3-carboxylic acid methyl ester (108, 2.3 g, 5.8 mmol) was combined with 30 mL of methanol and 10 mL of tetrahydrofuran under nitrogen and 10% palladium on carbon (0.23 g, 13.0 mmol) was added. The reaction was stirred under hydrogen at 1 atmosphere for 2 hours. The reaction was filtered and the filtrate concentrated under vacuum to provide the desired compound (109, 1.4 g).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[CH3:19][O:20][C:21]1[C:22](=[O:41])[C:23]([C:37](OC)=[O:38])=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH:26]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:37]([C:23]1[C:22](=[O:41])[C:21]([O:20][CH3:19])=[CH:26][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=2)[N:24]=1)=[O:38]
Reactant: CNOC
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(OC)c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (2.63 g, 27 mmol) and iPr2NEt (4.70 mL, 27 mmol) in CH2Cl2 (30 mL) was added AlMe3 (1.8 M solution in toluene, 15 mL, 27 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (2.95 g, 9 mmol) in CH2Cl2 (30 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (2.15 g, 67% yield) as off-white crystals: mp 170-171° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.71 (3H, s), 3.98 (3H, s), 7.63-7.71 (2H, m), 7.80-7.86 (1H, m), 7.88 (1H, s), 7.98 (1H, s). Anal. Calcd for C15H14F3N3O4: C, 50.42; H, 3.95; N, 11.76. Found: C, 50.48; H, 4.07; N, 11.66.
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].O=P(Cl)(Cl)[Cl:32]>>[Cl:32][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1
Reactant: COc1cccc(Nc2ncc(C#N)c(O)n2)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Nc2ncc(C#N)c(Cl)n2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxy-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile in POCl3 was added DMF 0.5 ml. The solution was refluxed for 3 h. The reaction mixture was cooled to room temperature and poured into ice-water. The solution was adjusted to pH=8-9 by aqueous sodium carbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo to afford 4-chloro-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.[Al](Cl)(CC)CC.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH:7]=[C:6]2[C:26](=[O:28])[CH3:27]
Reactant: COc1ccc(-n2ccc3cc(OC)ccc32)cc1
Reactant: CC(=O)Cl
Agent: CC[Al](Cl)CC
Solvent: ClCCl
Product: COc1ccc(-n2cc(C(C)=O)c3cc(OC)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
5-Methoxy-1-(4-methoxyphenyl)-1-H-indole (50 mg, 0.2 mmol), prepared by the method of example 1C, is dissolved in 1 mL of CH2Cl2 at 0° C. Et2AlCl (300 μL, 1M in hexanes, 0.3 mmol) is then added. After stirring at 0° C. for 30 min, a solution of acetyl chloride (22 μL, 0.3 mmol) in 1 mL of CH2Cl2 is added dropwise. This is stirred at 0° C. for a further 90 min. The reaction mixture is quenched with H2O and is extracted with CH2Cl2 and concentrated in vacuo. Purification by column chromatography on silica gel EtOAc/CH2Cl2 (5/95) yields the title compound as a white solid (42 mg, 71%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:12]=[C:13]([S:22][CH3:23])[N:14]=[N:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][CH:29]=[CH:28]2>C(#N)C>[CH3:23][S:22][C:13]1[N:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][CH:29]=[CH:28]3)[N:12]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1nnc(SC)nc1Nc1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Diisopropylethylamine (0.53 ml) was added to a solution of ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (234 mg) and 6-aminoquinoline (173 mg) in acetonitrile (3 ml), and the reaction solution was stirred in a microwave reactor at 100° C. for 1 hour. The solvent was evaporated under vacuum, and then the residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain ethyl 3-(methylthio)-5-(quinolin-6-ylamino)-1,2,4-triazine-6-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][C:31]=2[F:38])[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:32][C:31]=2[F:38])[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13]
Reactant: C1COCCN1
Reactant: CCN(c1cc(-c2ccc(C=O)cc2F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2′-fluoro-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (300 mg, 0.57 mmol) and morpholine (100 mg, 1.15 mmol) in dichloroethane (4 mL), acetic acid (207 mg, 3.46 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (367 mg, 1.73 mmol) was added to the reaction mixture at 0° C., allowed to attain room temperature and stirring continued for overnight. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (300 mg, 87.97%).
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccccn1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: c1ccc(B(OCc2ccccn2)C(OC(B(OCc2ccccn2)c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
The entitled compound (34 mg) was obtained by allowing 59 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 59 mg of 2-hydroxymethylpyridine to act in 0.7 mL of ethanol at room temperature.
Reaction SMILES: C([O:8][C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=[C:11]2[O:19][C@H:20]3[CH2:48][N:23]([C:24](=[O:47])[C@H:25]([CH:38]4[CH2:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH2:39]4)[NH:26][C:27](=[O:37])[O:28][C@@H:29]4[CH2:36][C@H:30]4[CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:10]=12)[C@H:22]([C:49]([O:51][CH3:52])=[O:50])[CH2:21]3)C1C=CC=CC=1>CO.C1COCC1.[Pd].C(OCC)(=O)C>[CH2:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46][CH:38]1[C@H:25]1[C:24](=[O:47])[N:23]2[CH2:48][C@@H:20]([CH2:21][C@H:22]2[C:49]([O:51][CH3:52])=[O:50])[O:19][C:11]2=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]([OH:8])=[C:10]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]2[CH2:36][C@H:29]2[O:28][C:27](=[O:37])[NH:26]1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1Cc3ccccc3C1)NC(=O)O[C@@H]1C[C@H]1CCCC#Cc1c(nc3ccccc3c1OCc1ccccc1)O2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1Cc3ccccc3C1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of the product of step 4 (480 mg, 0.686 mmol) in MeOH (9146 μl) and THF (4573 μl) was treated with a catalytic amount of 10% palladium on carbon (36 mg). The mixture was hydrogenated at 20 psi. After 2 hours LCMS showed >70% conversion. Hydrogenation was continued for another 2 h. LCMS showed >90% conversion. The mixture was diluted with ethyl acetate (50 mL) and the solids were removed by filtration. The filtrate was concentrated in rotavap and the residue was purified on a RediSep® (80 g) silica gel column (gradient: 0 to 50% ethyl acetate in hexanes) to give the title compound (420 mg, 0.684 mmol, 100% yield) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35]C(=O)C)=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>CO.ClCCl>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:32])[CH3:33])[CH2:25][CH2:26][CH:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[CH:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC1=C[C@@H]2[C@H](C(C)C)CCC(C)[C@]2(O)[C@@H](OC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)C1O
Yield: 97.7 %

Procedure:
To a stirred suspension of (1S,2R,4aS,5S,8R,8aR)-2-(acetyloxy)-8a-hydroxy-5-isopropyl-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydro-1-naphthalenyl-(2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Example 1, 887 mg) in methanol (25 ml) was added a solution of concentrated hydrochloric acid (1 ml) in methanol (25 ml). After 4 days the reaction mixture was diluted with dichloromethane (150 ml) and washed with water (3×100 ml). The combined aqueous layers were washed with dichloromethane (25 ml). All the organic phases were combined, dried and concentrated to yield a yellow solid (802 mg). Purification was achieved by flash column chromatography on silica gel eluting with 1:1 ethyl acetate:hexane to give the product (604 mg).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][S:4][CH:3]=1.[Cl:16][C:17]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[C:19]([Cl:36])[N:18]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN1CCCC1=O.C(OCC)(=O)C>[Cl:16][C:17]1[C:22]([C:2]2[C:6]([C:7]3[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][S:4][CH:3]=2)=[CH:21][CH:20]=[C:19]([Cl:36])[N:18]=1
Reactant: CCNc1ncccc1-c1cscc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(Cl)nc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCNc1ncccc1-c1cscc1-c1ccc(Cl)nc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 6.3 %

Procedure:
A mixture of 3-bromo-4-(2-ethylaminopyridin-3-yl)thiophene [synthesis described above] (0.757 g), 2, 6-dichloro-3-tributylstannylpyridine (1.331 g), triphenylarsine (0.261 g), and trisdibenzylideneacetone dipalladium (0.092 g) in N-methylpyrrolidinone (3 mL) was heated at 100° C. for 48 hours. Tetrabutylammonium fluoride (1M in tetrahydrofuran, 3 mL) was added . After 2 hours, the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 3-(2,6-dichloropyridin-3-yl)-4-(2-ethylaminopyridin-3-yl)thiophene (0.059 g) which was used directly in the next step. To a solution of 3-(2,6-dichloropyridin-3-yl)-4-(2-ethylaminopyridin-3-yl)thiophene (0.059 g) in tetrahydrofuran (2 mL) was added sodium hexamethyldisilazide (1 molar in tetrahydrofuran, 1 mL). After 20 minutes, the reaction was quenched with methanol, diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 6-chloro-8-ethyl-thienyl[3',4':6,5]dipyrido[2,3-b:3',2'-f]azepine (0.024 g) mp 139-141° C.