Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc([N+](=O)[O-])cn1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCn1cc(N)cn1
Reaction time: 3 h
Yield: 99.5 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 150 mg dry weight) and a solution of 116a (1.11 g, 4.10 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 3 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×25 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 100% yield of 116b (985 mg) as an orange oil: 1H NMR (500 MHz, CDCl3) d 7.18 (s, 1H), 7.11 (s, 1H), 4.09 (t, 2H, J=5.5 Hz), 3.89 (t, 2H, J=5.5 Hz), 3.25 (br s, 2H), 0.86 (s, 9H), −0.32 (s, 6H). MS (ESI+) m/z 242.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:12][O:11][S:10](=[O:14])(=[O:13])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:16](I)[CH:17]=[CH2:18].[OH-].[Na+]>C(Cl)Cl>[CH2:18]([N:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)([CH3:15])[CH2:12][O:11][S:10]1(=[O:14])=[O:13])[CH:17]=[CH2:16]
Reactant: C=CCI
Reactant: CC1(c2cccc(Br)c2)COS(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCN1C(C)(c2cccc(Br)c2)COS1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of 4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (7.3 g, 25 mmol) in DCM (77 mL) was added allyl iodide (9.1 mL, 100 mmol, 4 eq), followed by BnBu3NCl (0.39 g, 1.3 mmol) and 40% NaOH (28 mL). The mixture was stirred at RT for 16 h. The organic layer was separated and the solvent was evaporated. Silica gel chromatography using 5-20% EtOAc/hexanes gave 8.3 g (100%) of 3-allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC5; R6=Me) as a colorless oil. 1H NMR (CDCl3) δ 7.64 (t, J=1.8 Hz, 1H), 7.46-7.54 (m, 2H), 7.31 (t, J=8.0 Hz, 1H), 5.77-5.89 (m, 1H), 5.19-5.33 (m, 2H), 4.38 (dd, J1=8.7 Hz, J2=23.7 Hz, 2H), 3.46-3.68 (m, 2H), 1.83 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:47]([CH3:48])=[CH:46][C:39]([O:40][C:41]([CH3:45])([CH3:44])[C:42]#[N:43])=[CH:38][C:37]=1[CH3:49]>>[C:42]([C:41]([O:40][C:39]1[CH:38]=[C:37]([CH3:49])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:47]([CH3:48])[CH:46]=1)([CH3:45])[CH3:44])#[N:43]
Reactant: Cc1cc(OC(C)(C)C#N)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC(C)(C)C#N)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-(4-bromo-3,5-dimethylphenoxy)-2-methylpropanenitrile following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.25 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:15])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=1.[CH3:16][P:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:19])=[O:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:15][C:5]1[N:4]=[N:3][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([P:17]([CH3:16])([CH3:19])=[O:18])=[CH:21][C:22]=2[O:27][CH3:28])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1nnc(Cl)c(Nc2ccccc2)n1
Reactant: COc1cc(P(C)(C)=O)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(P(C)(C)=O)ccc1Nc1nnc(Cl)c(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-phenyl-1,2,4-triazin-5-amine (1 mmol), 4-(dimethylphosphoryl)-2-methoxyaniline (1 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 h in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[CH2:11][CH2:10][C:9]3=[C:12]([C:17]([OH:19])=O)[S:13][C:14]([S:15][CH3:16])=[C:8]3[C:6]=2[N:7]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.C[N:27](C)C=O>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]2[CH2:11][CH2:10][C:9]3=[C:12]([C:17]([NH2:27])=[O:19])[S:13][C:14]([S:15][CH3:16])=[C:8]3[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2c(s1)CCc1c(C(=O)O)sc(SC)c1-2
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CCc1nc2c(s1)CCc1c(C(N)=O)sc(SC)c1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
2-Ethyl-4,5-dihydro-8-methylthiothieno[3,4-e]benzothiazole-6-carboxylic acid (0.47 g) was suspended in tetrahydrofuran (15 ml); oxalyl chloride (0.29 g) and then N,N-dimethylformamide (6 l) were added. After this mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (8 ml); this suspension was added to a solution of diethyl 4-aminobenzylphosphonate (0.40 g), triethylamine (0.17 g) and tetrahydrofuran (15 ml) at room temperature. After the reaction mixture was stirred at room temperature for 1 hour, it was poured over water (150 ml) and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield N-[4-]diethoxyphosphorylmethyl)phenyl]-2-ethyl-4,5-dihydro-8-methylthiothieno[3,4-e]benzothiazole-6-carboxamide (0.69 g, 85%), which was then recrystallized from ethanol-hexane. Yellow needles. Melting point 179-180° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1.[H][H]>C(O)C.[Pd].[Ni]>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1cccc(OCCCCl)c1
Reactant: [H][H]
Agent: [Ni]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(OCCCCl)c1

Procedure:
Under a nitrogen atmosphere, a solution of 1-(3-chloropropoxy)-3-nitrobenzene (7.90 g, 36.64 mmol) in ethanol was added to 10% palladium on carbon in a Parr hydrogenation bottle. The mixture was hydrogenated on a Parr shaker. Because of very little hydrogen uptake, Raney® nickel (50% slurry in water) was carefully added to the reaction mixture and hydrogenation continued. When hydrogenation was complete the mixture was filtered through a mat of Celite® filter aid. The filtrate was concentrated on a rotary evaporator to an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[Li].C1C=CC=CC=1.[C:17]([CH2:21][CH2:22][C:23](Cl)=[O:24])([O:19][CH3:20])=[O:18].[Cl-].[NH4+]>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:23]([CH2:22][CH2:21][C:17]([O:19][CH3:20])=[O:18])=[O:24]
Reactant: [Li]c1c(F)cccc1OC
Reactant: COC(=O)CCC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)CCC(=O)c1c(F)cccc1OC

Procedure:
A cold solution of 2-fluoro-6-methoxylithiobenzene in ether was added to a cold dilute benzene solution of β-carbomethoxypropionyl chloride and the resulting complex was decomposed with ammonium chloride solution to give methyl 3-(2-fluoro-6-methoxybenzoyl)propionate.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.[BrH:21].N([O-])=O.[Na+]>O>[Br:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2N)cc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)c1ccc(-c2ccccc2Br)cc1

Procedure:
To 11.1 g. (0.044 moles) of ethyl 2'-amino-4-biphenylylglycolate suspension in 225 ml. of 40% hydrobromic acid and cooled to 0°C is added dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. of water. To this mixture is added a solution of 20 g. of cuprous bromide in 350 ml. of 40% hydrobromic acid added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water, extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is then crystallized to obtain 2'-bromo-4-biphenylylglycolic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1cccc2cccnc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccc([N+](=O)[O-])c2cccnc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.5 %

Procedure:
To a solution of commercially available 8-methylquinoline (5.0 g, 34 mmol) in concentrated H2SO4 (19 mL) at 0° C. was added portionwise KNO3 (4.29 g, 42.4 mmol). After the addition, the reaction was stirred at rt for 17 h, then poured into ice/water and extracted with EtOAc (3×100 mL). The aqueous layer was basified to pH=9 with solid Na2CO3 and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) to yield the title compound (5.98 g, 94%) as a light yellow solid. LC/MS m/z 189 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:32])C=CC=CC=1>C(Cl)(Cl)Cl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:32])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOCCOc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOCCOc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (289 mg, 0.83 mmol) in chloroform (5 mL) was added 2-benzenesulfonyl-3-phenyl-oxaziridine (281 mg, 1.07 mmol). The reaction mixture was stirred at RT overnight, under nitrogen. The solvents were removed and the crude product was chromatographed on silica gel, eluting with a 5% methanol-ethyl acetate/hexane gradient to give 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one as a clear oil (210 mg, 0.56 mmol). 1H NMR δ(400 MHz, CDCl3) 8.84 (s, 1H), 6.89 (s, 1H), 6.06-5.98 (m, 1H), 4.23 (t, J=4.0 Hz, 2H), 3.89 (t, J=4.0 Hz, 2H), 3.60 (q, J=6.9 Hz, 2H), 2.95 (s, 3H), 2.28-2.19 (m, 2H), 2.15-2.10 (m, 2H), 1.97-1.88 (m, 2H), 1.71-1.64 (m, 2H), 1.21 (t, J=6.9 Hz, 3H); MS (APCI+) 350 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1I)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:26]=[C:27]([C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])[CH2:8][CH3:9])[C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH3:21]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCN(Cc1cc(Br)ccc1I)C(=O)OC(C)(C)C
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (5-bromo-2-iodo-benzyl)-ethyl-carbamic acid tert-butyl ester and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: O[CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C(Cl)Cl>[I:41][CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: II
Reactant: C[C@@H](CO)CN1C(=O)COc2ccccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](CI)CN1C(=O)COc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.4 %

Procedure:
A reaction flask was charged with (R)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (1.71 g, 7.77 mmol), triphenylphosphine (4.50 g, 17.2 mmol), imidazole (1.27, 18.7 mmol), and iodine (5.54 g, 21.8 mmol) in CH2Cl2 (20 mL) and stirred at rt for 20 h. The reaction mixture was washed with saturated sodium thiosulfate, dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (2.25 g, 87%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.C[O-].[Na+].CO.[CH2:29]([C:31]1[CH:32]=[CH:33][C:34]([CH:37]=O)=[N:35][CH:36]=1)[CH3:30].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:29]([C:31]1[CH:32]=[CH:33][C:34]([CH2:37][NH:2][CH:3]2[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:23])[CH2:7][CH2:8]2)=[N:35][CH:36]=1)[CH3:30]
Reactant: CCc1ccc(C=O)nc1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(CNC2CCN(CCn3c(=O)ccc4ncc(OC)cc43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a suspension of 0.20 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 2 mL of methanol, 0.28 g of a 28% sodium methoxide/methanol solution, 66 mg of 5-ethylpyridine-2-carbaldehyde and 28 μL of acetic acid were added. Then, 61 mg of sodium cyanoborohydride was added thereto and the mixture was stirred at room temperature for 3 hours. Thereto was further added 31 mg of sodium cyanoborohydride, and the mixture was stirred at room temperature for 1 hour 30 minutes. To the reaction mixture, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using gradient elution with chloroform:methanol=93:7 to 9:1 to obtain 0.15 g of 1-(2-(4-(((5-ethylpyridin-2-yl)methyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one as a light yellow oily substance.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[Cl:20][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:19])[C:14]3[C:15]([OH:17])=[N:30][N:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[C:3](=[O:4])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: NNc1ccc(F)cc1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(F)cc3)nc(O)c12
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (2.59 g, 8.79 mM) and 4-fluorophenylhydrazine hydrochloride (10.0 g, 61.5 mM) in ethanol (48 mL) was added triethylamine (9.8 mL, 70.3 mM). The resulting brown solution was refluxed for 48 hours, cooled to room temperature and diluted with ethyl acetate (150 mL) to give a white crystalline precipitate which was removed by filtration and discarded. The filtrate was washed with hydrochloric acid (3×500 mL, 1N) which caused precipitation in the ethyl acetate layer. The precipitate was collected and washed successively with ethyl acetate/ether and ether to give the 4-fluorophenylhydrazine salt of the title compound (2.14 g). This material was refluxed in glacial acetic acid (20 mL) for 2 hours. After cooling the acetic acid solution to room temperature, a precipitate formed and the solids were collected to give the title compound (1.48 g, 47%) as a yellow powder, mp 390-392° C.; MS(CI): 358 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[CH:18]=[C:17]([C:19]3[O:20][CH:21]=[C:22]([C:24](=[O:41])[NH:25][C:26]4[C:27]([N:32]5[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][OH:39])[C:33]5=[O:40])=[N:28][N:29]([CH3:31])[CH:30]=4)[N:23]=3)[CH:16]=[CH:15][N:14]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C(OC(=O)C)C.Cl>CO>[CH:1]1([CH2:4][NH:5][C:13]2[CH:18]=[C:17]([C:19]3[O:20][CH:21]=[C:22]([C:24]([NH:25][C:26]4[C:27]([N:32]5[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][OH:39])[C:33]5=[O:40])=[N:28][N:29]([CH3:31])[CH:30]=4)=[O:41])[N:23]=3)[CH:16]=[CH:15][N:14]=2)[CH2:2][CH2:3]1
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC4CC4)C(=O)OC(C)(C)C)c3)n2)c(N2CCN(CCO)C2=O)n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(NCC4CC4)c3)n2)c(N2CCN(CCO)C2=O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A mixture of tert-butyl (cyclopropylmethyl)(4-(4-((3-(3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)carbamate (208 mg), 4M hydrogen chloride ethyl acetate solution (5 mL) and methanol (5 mL) was stirred at 50° C. for 1 hr, the reaction mixture was cooled, and the solvent was evaporated under reduced pressure. The residue was dissolved in water, and the solution was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (130 mg).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[C:32](O)(=[O:35])[CH:33]=[CH2:34].COC1C=CC(O)=CC=1>C1(C)C=CC=CC=1>[CH:10]1[C:11]2[N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:32](=[O:35])[CH:33]=[CH2:34])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC(=O)O
Reactant: OCCCCCCn1c2ccccc2c2ccccc21
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C

Procedure:
To a 500 ml three-neck round bottom flask was added 33 g. of 6-carbazol-9-yl-hexan-1-ol, 170 g. toluene, 2.2 g. PTSA, 10.7 g. acrylic acid and 0.07 g. hydroquinone monomethyl ether (MEHQ). The mixture was heated to reflux and the water was removed by azeotropic distillation using a Dean-Stark trap. After five hours of reflux, 1 gram additional acrylic acid was added and the mixture heated for one additional hour. The reaction mixture was cooled to room temperature, washed with 100 g 5% HCl in water, then 100 g. 10% sodium carbonate in water, then 100 g. of saturated brine. The solvent was removed on a rotary evaporator.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].OO.C(=[O:20])CCCCCCC>[Pt]>[C:1]([OH:20])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC=O
Reactant: CCCCCCCCO
Agent: [Pt]
Agent: OO
Product: CCCCCCCC(=O)O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
Platinum black (19.5 mg, 0.100 mmol) and 1-octanol (1.6 ml, 10 mmol) were mixed and stirred at 90° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (1.3 ml, 12 mmol) was gradually added dropwise to the mixed solution, followed by stirring at 90° C. for 5 hours, and then the reaction solution was cooled to room temperature. As a result of measurement by GLC, it was found that 1-octanal was obtained in yield of 18%, and 1-octanoic acid was obtained in yield of 19%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[I:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=C1CCC(n2cc(I)ccc2=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(I)ccc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-iodo-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[C:4]([C:23]([O:25][CH3:26])=[O:24])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[C:9]([C:21]#[N:22])[CH:8]=1.C(N(CC)CC)C>O1CCOCC1.[C].[Pd]>[C:21]([C:9]1[CH:8]=[C:7]([C:6]2[S:5][C:4]([C:23]([O:25][CH3:26])=[O:24])=[C:3]([F:27])[CH:2]=2)[CH:12]=[CH:11][C:10]=1[OH:13])#[N:22]
Reactant: COC(=O)c1sc(-c2ccc(OCc3ccccc3)c(C#N)c2)c(Br)c1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1sc(-c2ccc(O)c(C#N)c2)cc1F

Procedure:
(4-Benzyloxy-3-cyanophenyl)boronic acid and methyl 4,5-dibromo-3-fluorothiophene-2-carboxylate were dissolved in a mixed solution of toluene and a 1M aqueous sodium carbonate solution and the whole was heated at 110° C. for 2.5 days in the presence of tetrakis(triphenylphosphine)palladium to obtain methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate. Methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate and triethylamine were stirred at room temperature in 1,4-dioxane under a hydrogen atmosphere at normal pressure in the presence of palladium-carbon to obtain methyl 5-(3-cyano-4-hydroxyphenyl)-3-fluorothiophene-2-carboxylate. FN: 276.