Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[O:18][CH:19]([CH3:21])[CH3:20])=[O:7])[CH2:3]1.F[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:19]([O:18][C:9]1[CH:10]=[CH:11][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:13][C:8]=1[C:6]([N:4]1[CH2:5][CH:2]([O:1][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:3]1)=[O:7])([CH3:21])[CH3:20]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1

Procedure:
A mixture of 0.32 mmol (3-hydroxy-azetidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone, 0.32 mmol 4-fluoro-benzotrifluoride and 0.96 mmol cesium carbonate in 10 ml acetonitrile was refluxed overnight. The reaction mixture was concentrated to yield the crude compound, purified by chromatography (methanol/dichloromethane). MS (m/e): 458.4 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3C=C[C:17]([CH2:20][CH2:21]C(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC([C:45]2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3[N:46]=2)=C(OCC2CCCC2)C=1.BrCC1C=C(C=CC=1)C#N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:17]=[CH:20][CH:21]=3)[C:45]#[N:46])[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Agent: N#Cc1cccc(CBr)c1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(C#N)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 3-bromomethyl-benzonitrile (CAS Reg. No. 28188-41-2). Brown solid (72%). MS (Turbo Spray): m/z=410.2 (M+H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH2:6]([N:13]=[C:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+]>ClCCl>[CH2:3]([C:14]1([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:23][CH2:22][C:17]2([O:18][CH2:19][CH2:20][O:21]2)[CH2:16][CH2:15]1)[CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: c1ccc(CN=C2CCC3(CC2)OCCO3)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCC1(NCc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 1 M solution of allylmagnesium bromide (127 ml, 127 mmol) was added dropwise to a solution of benzyl-(1,4-dioxaspiro[4.5]dec-8-ylidene)amine (15.6 g, 63.7 mmol) in dichloromethane (120 ml), and the reaction mixture was stirred for 72 h at room temperature. The mixture was then poured carefully onto saturated ammonium chloride solution (100 ml), while cooling with ice, and extraction with dichloromethane (3×40 ml) was carried out. The combined organic phases were dried with sodium sulfate and concentrated in vacuo, and the residue was purified by flash chromatography (400 g, 20×7.6 cm) with chloroform/methanol (10:0.2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.O=[CH:23][CH2:24][NH:25]C(=O)OC(C)(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C.C(#N)C>[NH2:25][CH2:24][CH2:23][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC#N
Product: NCCNc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Temperature: 170 °C

Procedure:
A solution of EXAMPLE 12 (0.06 g, 0.2 mmol) and tert-butyl (2-oxoethyl)carbamate (0.035 g, 0.2 mmol) in ethanol (1 mL) and acetonitrile (1 mL) was treated with sodium cyanoborohydride (0.014 g, 0.2 mmol) and acetic acid (0.2 mL). The mixture was heated in a microwave at 170° C. for 40 minutes and concentrated. The residue was purified by flash chromatography on silica gel with 10% methanol/dichloromethane/0.1% ammonium hydroxide to provide the title compound. 1H NMR (DMSO-d6) δ 12.30 (s, 1H), 10.06 (s, 1H), 8.11-8.19 (m, 2H), 7.89-7.96 (m, 1H), 7.58-7.67 (m, 2H), 7.52 (t, J=7.6 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 6.27 (s, 1H), 3.30-3.36 (m, 4H), 2.08 (s, 3H).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].OS(O)(=O)=O>N1C=CC=CC=1>[Si:28]([O:22][CH2:21][CH:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:20])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Compound 2a (2.297 g, 7.26 mmol) was dissolved in anhydrous pyridine (20 mL) at RT under argon. Imidazole (1.02 g, 14.52 mmol) in anhydrous pyridine (10 mL) was the added followed by tert-butyl dimethylsilyl chloride (TBDMS-Cl, 2.25 g, 14.52 mmol) in anhydrous pyridine (20 mL). The reaction mixture was stirred at RT for 72 hours, poured into 0.5 M H2SO4 (150 mL) and extracted with diethyl ether (100 mL, 3×), The extract was washed successively with saturated aqueous NaHCO3 (100 mL) and water (100 mL), dried over anhydrous Na2SO4 and the solvent removed under reduced pressure to obtain 3a, an oily material which was dried in a vacuum dessicator for 2 days (3.164 g, 100% yield). 1H NMR (in CDCl3): δ in ppm 0.83-0.89 (15H, m), 1.22 (29H, m), 1.52-1.53 (2H, m), 2.60 (1H, s, D2O exchangeable), 3.40-3.42 (4H, m), 3.59-3.61 (2H, m), 3.64 (1H, m); 13C NMR (in CDCl3): δ in ppm 14.3, 18.2, 18.5, 22.9, 25.8, 26.0, 26.1, 26.3, 29.6, 29.8, 29.9, 32.1, 33.0, 64.2, 70.8, 71.6, 71.9.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: NNc1cccc(F)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2cccc(F)c2)n1
Yield: 66.5 %

Procedure:
The title compound was prepared from 3-Fluorophenylhydrazine hydrochloride (1.30 g, 8.0 mmol) and 4,4-Dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedure in Example 161A Step 3 to give 3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-amine (1.24 g, 5.32 mmol, 67%). 1H NMR (300 MHz, DMSO-d6) δ 7.49-7.41 (m, 3H), 7.10 (br s, 1H), 5.41 (s, 1H), 5.35 (br s, 2H), 1.21 (s, 9H); LC-MS (ESI) m/z 234 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14](=[O:27])[C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][C:18]([CH3:26])([CH3:25])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1COCC1.[BH4-].[Na+].Cl>CO>[OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]([OH:27])[C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][C:18]([CH3:25])([CH3:26])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCC3)cc1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.95 g (22 mol) of methyl 2-hydroxy-4-[3-oxo-3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl]benzoate, 150 ml of THF and 20 ml of methanol are introduced into a round-bottomed flask. 660 mg (17.4 mmol) of sodium borohydride are added portionwise and the mixture is stirred at room temperature for two hours. The reaction medium is poured into ice-water, neutralized with hydrochloric acid and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvents, 3.8 g (47.5%) of the expected product are collected in the form of an oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[CH:4][C:5]2[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][C:6]=2[CH:21]=1.[CH2:23]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34](OB(O)O)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:23]([O:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([C:2]2[C:3]([CH3:22])=[CH:4][C:5]3[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][C:6]=3[CH:21]=2)=[CH:35][CH:36]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)C1=Cc2cc(Br)c(C)cc2N(CC(C)C)CCC1
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2cc3c(cc2C)N(CC(C)C)CCCC(C(=O)OC)=C3)cc1
Reaction time: 1 h
Yield: 67 %

Procedure:
A suspension of methyl 8-bromo-1-isobutyl-9-methyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (900 mg) and 4-(2-butoxyethoxy)phenyl boric acid (759 mg) and potassium carbonate (883 mg) in toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under argon atmosphere for 1 hour. Then, tetrakis(triphenylphosphine)palladium (142 mg) was added and the mixture was refluxed for 6 hours. After returning to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1→6:1) to give methyl 8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-9-methyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (790 mg) as a yellow oily material.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[S:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)[CH:11]=1>>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:11]=[C:10]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[S:18][C:17]=34)=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: Brc1cc2nccc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: OB(O)c1cccs1
Product: c1csc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)c1

Procedure:
The title compound was prepared from thiophene-2-boronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 17. 1H NMR (400 MHz, DMSO) d 11.1 (s, 2H), 8.27 (d, 1H), 7.73 (s, 1H), 7.48 (m, 5H), 7.19 (m, 1), 7.03 (d, 1H), 6.50 (s, 1H); LC-MS: 348 (MH+); HPLC RT: 5.11 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[C:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:18]=[C:17]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])[C:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:15][C:11]=2[C:12]([NH:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: Nc1cccnc1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccc(F)cc3)cc2C(=O)N2CCOCC2)cn1
Reaction time: 18 h

Procedure:
To a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)benzoic acid (may be prepared as described in Description 29; 12 mg, 0.02 mmol) in N,N-dimethylformamide (4 ml), was added diisopropylethylamine (4.15 μL, 0.02 mmol), 3-aminopyridine (2.23 mg, 0.02 mmol) and HATU (9.03 mg, 0.02 mmol). The reaction stirred for 18 hours, then the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a gum. 4.8 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]=[C:10]2[CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C:20]1[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.C([O-])(=O)C.[Na+].[Br:33]Br>C(O)(=O)C>[Br:33][C:13]1[C:14](=[O:15])[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][C:3]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:2]([F:1])[CH:7]=2)[C:10]([CH2:17][CH2:18][CH3:19])=[N:11][C:12]=1[CH3:16]
Reactant: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)c(F)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To a mixture of 2′-fluoro-4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.78 g), sodium acetate (0.19 g) and acetic acid (10 mL) was added bromine (0.12 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated from the reaction mixture under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.54 g, 57%).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Br[C:20]1[S:24][C:23]([C:25]#[N:26])=[N:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:25]([C:23]1[S:24][C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:21][N:22]=1)#[N:26]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: N#Cc1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C#N)s3)cc(C)c21
Temperature: 60 °C
Yield: 84 %

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.35 g, 5.4 mmol, 1 eq.) and 5-bromo-1,3,4-thiadiazole-2-carbonitrile (1.54 g, 8.1 mmol, 1.5 eq.) in 50 ml ACN was added potassium carbonate (2.24 g, 16.2 mmol, 3 eq.). The reaction was heated at 60° C. for three hours. The reaction was quenched by water, acidified to pH=3 with 1N HCl and then extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography to give desired product as yellow oil (1.63 g, yield 84%). MS (ESI) m/z=718 [2M+H]+.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:27]4[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=4[O:37][CH3:38])=[CH:25][CH:24]=[C:23]([C:39]([CH3:41])=[CH2:40])[N:22]=3)[C@@H:15]([CH3:42])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H][H]>CCO.[Pd]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:27]4[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=4[O:37][CH3:38])=[CH:25][CH:24]=[C:23]([CH:39]([CH3:41])[CH3:40])[N:22]=3)[C@@H:15]([CH3:42])[CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:8]=1
Reactant: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@@H]2C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(C)C)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one (Example 5, 8.0 mg, 0.011 mmol) in EtOH (2 mL) was charged with hydrogen at 1 atm with catalytic amount of Pd/C. The mixture was stirred at room temperature for 1 h. The mixture was filtered through Celite and concentrated. The title compound was obtained after flash chromatography on silica gel using EtOAc:hexane 10:90 as the elute to afford 4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropylpyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one. LCMS=627.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.86 (s, 3H), 7.68 (brs, 1H), 7.18 (brs, 1H), 7.14 (br m, 1H), 6.71 (d, J=11.9 Hz, 1H), 5.31-5.27 (m, 2H), 4.31-4.24 (m, 2H), 3.80 (s, 3H), 2.21 (m, 1H), 1.82 (m, 1H), 1.26 (br s, 3H), 1.21 (br m, 12H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([NH:11]C(=O)C(F)(F)F)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-].[Na+]>C(O)C>[NH2:11][C:5]1[C:4]([N+:18]([O-:20])=[O:19])=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 5-fluoro-3-nitro-2-(2,2,2-trifluoroacetamido)benzoic acid (141; 1.2 g, 4.1 mmol) in ethanol (20 mL) was added 10% aqueous sodium hydroxide solution (20 mL). The resulting reaction mixture was stirred at 80° C. for 3 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting orange solids were acidified with dilute HCl, filtered and dried to afford 2-amino-5-fluoro-3-nitrobenzoic acid 142 (0.73 g, 90%).
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=O)[CH3:2].[CH:8]([C:11]1[C:12]([NH2:17])=[N:13][NH:14][C:15]=1[NH2:16])([CH3:10])[CH3:9].Cl.NO>C(O)(=O)C>[CH:8]([C:11]1[C:15]([NH2:16])=[N:14][N:13]2[C:1]([CH3:2])=[CH:4][C:5]([CH3:6])=[N:17][C:12]=12)([CH3:10])[CH3:9]
Reactant: CC(C)c1c(N)n[nH]c1N
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: NO
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(N)c(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of acetylacetone (1034 mg, 10.33 mmol) and the product from Example 112B (965 mg, 6.88 mmol) in acetic acid (5 mL) was heated at 115° C. for 90 minutes, and then cooled to room temperature. Hydroxylamine hydrochloride (520 mg) was added, and the solution was stirred at room temperature for 14 hours, and then concentrated under vacuum. The residue was purified by HPLC (30×100 mm XBridge column eluted with 0.1 M aqueous (NH4)2CO3-MeOH, 60:40-0:100 over 15 min) to provide the title compound. MS (DCI/NH3) m/z 205 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH:16]2[CH2:17][O:18][CH2:19][CH:9]1[C:10]1[CH:11]=[N:12][O:13][C:14]=1[CH:15]2[F:20])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:20][CH:15]1[CH:16]2[NH:8][CH:9]([CH2:19][O:18][CH2:17]2)[C:10]2[CH:11]=[N:12][O:13][C:14]1=2
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(F)c1oncc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1c2oncc2C2COCC1N2
Yield: 145.1 %

Procedure:
A solution of 7-Fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylic acid tert-butyl ester (150 mg) in TFA/DCM (5 mL, 1:2) was stirred at room temperature for 1 h. The solvent was removed in vacuo to give 7-fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 106a (141 mg) as yellow oil, crude yield: 100%. MS: calc'd (MH+) 185, measured (MH+) 185.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].CO.[OH-].C[N+](C)(C)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)C1C=CC=CC=1>C(Cl)Cl.O1CCCC1>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: CSCS(C)=O
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O=Cc1ccccc1
Solvent: CO
Product: CSC(=Cc1ccccc1)S(C)=O
Yield: 91 %

Procedure:
FAMSO (2.572 g), 3 ml of a 40% methanol solution of trimethylbenzylammonium hydroxide, and 3 ml of benzaldehyde were added to 5 ml of tetrahydrofuran, and the mixture was refluxed for 4 hours. After adding 100 ml of methylene chloride, the reaction mixture was washed with dilute sulfuric acid. The product was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel using methylene chloride as an eluant to afford 3.994 g of 1-methylsulfinyl-1-methylthio-2-phenylethylene as a colorless liquid having a boiling point of 149° to 150° C./0.08 mmHg in a yield of 91.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH2:19]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH:20]=[CH2:21].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:21][CH:20]([CH2:19][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Cl)cc1
Reactant: C=CCP(=O)(OCC)OCC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC1CC(c2ccc(Cl)cc2)=NO1)OCC
Yield: 104.5 %

Procedure:
Preparation is carried out as in Example 1 from 23.34 g of 4-chlorobenzaldoxime, 22 g of N-chlorosuccinimide, 29.5 g of diethyl allylphosphonate and 22.9 ml of triethylamine in dichloromethane and provides 52 g of oily product.
Reaction SMILES: CN1CCN([C:8]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16](=[CH2:23])[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[CH:9]=2)CC1.[OH-:24].[Na+]>Cl>[CH2:23]=[C:16]1[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[CH2:9][C:8](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]1=2
Reactant: C=C1c2cnccc2C=C(N2CCN(C)CC2)c2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: C=C1c2cnccc2CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product from Step D (10.76 g.) and 3N HCl (150 ml.) is stirred at room temperature for approximately 24 hours. The dark brown solution is made alkaline by the addition of 20% NaOH solution and extracted with methylene chloride. The extracts are washed with H2O, saturated NaCl solution and dried (Na2SO4). Removal of the solvent in vacuo followed by trituration with petroleum ether (30°-60°) provides 6.2 g., m.p. 98°-110° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH:28]=4)[CH2:25][C:24](=[O:40])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
The title compound was prepared from {4-(4-fluoro-phenylethynyl)-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M147) (287 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (197 mg, 88%).