Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:31]([C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1)[CH3:32]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[N:12]([CH:31]([C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])=[CH:35][CH:34]=3)[CH3:32])[N:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Br)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Clc1cc(Cl)cc(-c2cc(-c3ccc4nccnc4c3)n[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(C(=O)OC(C)(C)C)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate from step E (330 mg, 0.97 mmol) in 8 mL of anhydrous DMF was added Cs2CO3 (473 mg, 1.45 mmol) followed by tert-butyl 4-(1-bromoethyl)benzoate (331 mg, 1.16 mmol). The reaction was stirred at room temperature overnight and then diluted with water. The aqueous layer was then extracted with EtOAc (3×) and the combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography (20% EtOAc/Hexanes) to give the product as a yellow oil. 1H NMR (CDCl3, 500 MHz): 1.60 (s, 9H), 2.02 (d, J=7.1 Hz, 3H), 5.67 (q, J=7.1 Hz, 1H), 6.78 (s, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.34 (t, J=1.8 Hz, 1H), 7.68 (dd, J=8.7, 1.9 Hz, 1H), 7.83 (d, J=1.8, 2H), 7.95 (d, J=8.2 Hz, 2H), 8.10 (d, J=1.9, 1H), 8.18 (d, J=8.7, 1H), 8.94 (s, 2H). LC-MS: 4.74, 4.89 min. (M+H)=546.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24](O)=[O:25])=[CH:20][NH:21]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]([N:11]3[CH2:12][CH2:13][N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH2:9][CH2:10]3)=[O:25])=[CH:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Product: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1

Procedure:
Following general procedure I, the coupling of (commercially available) 1-(2-fluoro-phenyl)-piperazine (described herein) with 6-chloro-1H-indole-3-carboxylic acid gave the title compound.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(OCC)(=O)C>[CH:17]1[CH:16]=[CH:15][C:14]([N:7]([C:1]2[CH:2]=[CH:3][C:4]([Br:20])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 1-L Erlenmeyer flask, 25 g (100 mmol) of triphenylamine, 18 g (100 mmol) of N-bromosuccinimide, and 400 mL of ethyl acetate were put and stirred at room temperature in air for 24 hours. After the reaction, the reaction solution was washed twice with a saturated aqueous solution of sodium carbonate to separate into an aqueous layer and an organic layer. The aqueous layer was extracted twice with ethyl acetate and washed with saturated saline together with the organic layer. After the organic layer was dried with magnesium sulfate, natural filtration and enrichment was performed, and the resulting white solid was recrystallized with ethyl acetate and hexane, whereby 22 g of a white powder solid of 4-bromotriphenylamine was obtained at a yield of 66%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[NH2:15])[C:4]([CH3:16])=[N:3]1.C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:15][C:9]1[CH:10]=[C:11]([NH:14][C:31]([C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=2)=[O:32])[CH:12]=[CH:13][C:8]=1[C:5]1[C:4]([CH3:16])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1nn(C)c(C)c1-c1ccc(N)cc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C)c(C)c1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a solution of 76 (119.4 mg, 0.55 mmol) in CH2Cl2 (20 ml) was added N,N-diisopropylethylamine (DIEA, 258 mg, 348 μL, 2 mmol), 4-dimethylaminopyridine (DMAP, 0.6 mg, 0.05 mmol). The 4-chlorobenzoyl chloride (96 mg, 0.55 mmol) was dropped into above solution. The mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (40 ml) and extracted with EtOAc. The dicarboxamide was hydrolyzed with 1M NaOH in THF and MeOH (1:1). The product was purified by HPLC and afforded 77 (49 mg, 25%) as yellow solid. LC-MS: calcd. for C19H19ClN4O: 355 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([O:20][C:18]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccccc1CNC(=O)OCc1ccccc1

Procedure:
To a solution of 3.0 g (9.64mmol) tert-butyl [2-(aminomethyl)phenyl]acetate in 100 mL methylene chloride cooled to 0° C. was added 0.825 ml (5.78 mmol) benzyl chloroformate followed by 1.47 g (12.05 mmol) of 4-dimethylaminopyridine and a second 0.825 ml (5.78 mmol) portion of benzyl chloroformate. After 30 min the reaction was washed with 10% potassium hydrogen sulfate (aq) (2×30 mL), water (1×30 mL), and brine (1×30 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The resulting crude oil (3.69 g) was flash chromatographed on silica gel (15% ethyl acetate in hexane) to give tert-butyl [2-({[(benzyloxy)carbonyl]amino}methyl)phenyl]acetate as a colorless oil: 1H NMR (CDCl3, 400 MHz): δ7.38-7.30 (m, 5H), 7.28-7.21 (m, 4H), 5.40 (br s, 1H), 5.12 (s, 2H), 4.40 (d, 2H, J=5.5 Hz), 3.61 (s, 2H), 1.41 (s, 9H); MS (Electrospray): M+Na=378.1; TLC Rf=0.30 (15% ethyl acetate in hexane).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C(N(CC)CC)C.[C:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])[CH3:26]>C(Cl)Cl.CCCCCC>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([N:15]2[C@H:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@H:29]([O:28][C:25](=[O:27])[CH3:26])[C:30]2=[O:31])=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(N2C(=O)[C@@H](OC(C)=O)[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 962 mg (4.56 mmol) of the imine derived from benzaldehyde and p-methoxy aniline, and 0.85 mL (6.07 mmol) of triethylamine in 15 mL of CH2Cl2 at -20° C. was added dropwise a solution of 413 mg (3.04 mmol) of α-acetoxy acetyl chloride in 15 mL of CH2Cl2. The reaction mixture was allowed to warm to 25° C. over an 18 h period. The reaction mixture was then diluted with 100 mL of CH2Cl2 and the solution was extracted with 30 mL of 10% aqueous HC1. The organic layer was washed with 30 mL of water and 30 mL of saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated to provide a solid mass. The solid was titurated with 50 mL of hexane and the mixture was filtered. The remaining solid was recrystallized from ethyl acetate/hexane to give 645 mg (68%) of cis-1-p-methoxyphenyl-3-acetoxy-4-phenylazetidin-2-one as white crystals, m.p. 163° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[NH:5]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[NH2:5]
Reactant: COC(=O)[C@H](CSc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)[C@@H](N)CSc1ccc([N+](=O)[O-])cc1

Procedure:
Crude II from Step B is taken up in 2 ml anisole and then treated at 0° C. for 11 minutes with 10 ml of TFA. The TFA and anisole are pumped off at 0.1 Torr at 30° C. and the residue partitioned between chloroform and aqueous 1 N HCl. The aqueous layer is made to pH 9.0 with NaOH and extracted with CH2Cl2, providing a solution of compound 3·III.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([OH:20])=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:43](N)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)C=O.O>[CH2:1]([N:8]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:9]([C:11]1[C:12](=[O:20])[NH:13][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cnc(O)c(C(=O)NCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1c[nH]c(=O)c(C(=O)N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a suspension of 5-benzylcarbamoyl-6-hydroxy-nicotinic acid 1.0 (3.67 mmol), EDAC.HCl 0.84 g (4.4 mmol), HOBT 0.59 g (4.4 mmol), in dimethylformamide (20 mL) was added benzylamine 0.47 g (4.4 mmol). The mixture was stirred overnight at room temperature. Water (20 mL) was added, and the reaction mixture was filtered. The solid product was then slurried in hot ethyl acetate. 1.1 g (81% yield). MS: m/z (APCI, AP+) 362.2 [M−]+. CHN Analysis: Calcd: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.49; H, 5.38; N, 11.64.
Reaction SMILES: IC.[Cl:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[C:7]2[NH:12][CH:13]=[N:14][C:6]=2[CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[C:7]2[N:12]([CH3:15])[CH:13]=[N:14][C:6]=2[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CSc1nc(Cl)cc2nc[nH]c12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)cc2ncn(C)c12
Reaction time: 1.5 h

Procedure:
Iodomethane (0.52 mL, 8.36 mmol) was added to a solution of 6-chloro-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.01 (1.40 g, 7.04 mmol) and potassium carbonate (1.95 g, 14.1 mmol) in 46 mL of DMF at room temperature. After 90 minutes, reaction mixture was taken up in ethyl acetate (150 mL) and washed with 50% saturated NaHCO3 (aq)(2×100 mL). After separating layers, aqueous was extracted with ethyl acetate (100 mL). All combined organic layers were washed with 50% brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield a solid. This was purified via silica gel column chromatography (5-25% acetone in hexanes) to yield 6-chloro-3-methyl-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.02 (first eluting product).
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([CH2:10][OH:11])[S:8][CH:9]=1>C(C#N)(C)=O.O=[Mn]=O>[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([CH:10]=[O:11])[S:8][CH:9]=1
Reactant: OCc1nc(CCl)cs1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: O=Cc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-chloromethyl-thiazol-2-yl)-methanol (1.60 g, 9.80 mmol) in AcCN (98.0 mL) was treated at rt with MnO2 (4.73 g, 49.01 mmol). The reaction mixture was stirred at rt overnight before being filtered through Celite and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a colorless oil. TLC:rf (4:1 hept-EA)=0.37. LC-MS-conditions 02: tR=0.77 min.
Reaction SMILES: OCC1C=CC(C[NH:8][C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=CC=1.S(Cl)(Cl)=O.O>CN(C=O)C.[Cl-].[Na+].O>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=[C:11]1[C:9]([NH2:8])=[O:10]
Reactant: O=C(NCc1ccc(CO)cc1)c1c[nH]c2ccccc2c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(hydroxymethyl)benzyl] 4-oxo-1,4-dihydro-quinoline-3-carboxamide (279 mg; 0.79 mmol) in anhydrous DMF (8 mL) at 0° is added thionyl chloride (61 μL; 0.83 mmol) and the solution is stirred at room temperature for 1 h. Water (10 mL) and brine (10 mL) are added, and the precipitate is collected, rinsed with a small quantity of methanol and ether, and dried to give 214 mg of N-[4-chloromethyl)benzyl] 4-oxo-1,4-dihydro-quinoline-3-carboxamide.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[C:4]([CH3:18])[C:5]2[C:10]([C:11]=1[C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([OH:17])[CH:6]=2.[OH:22][CH2:23]C1C(C(O)=O)=CC2C(C=1C1C=CSC=1)=CC=C(O)C=2>>[OH:22][CH2:23][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[CH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([OH:17])[CH:6]=2.[OH:1][C:2]1[C:3]([C:19]([OH:21])=[O:20])=[C:4]([CH3:18])[C:5]2[C:10]([C:11]=1[C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([OH:17])[CH:6]=2
Reactant: O=C(O)c1cc2cc(O)ccc2c(-c2ccsc2)c1CO
Agent: Cc1c(C(=O)O)c(O)c(-c2ccoc2)c2ccc(O)cc12
Product: O=C(O)c1cc2cc(O)ccc2c(-c2ccoc2)c1CO

Procedure:
Following the procedure described in Example 7, but substituting (1S,5R) 3-[3-(3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]benzyl alcohol (Alcohol 3) for 5-[4-(4-hydroxy)tetrahydropyranyl]pyridin-3-ylmethanol (Alcohol 1), and substituting 3-hydroxymethyl-4-(3-thienyl)-7-hydroxy-2-naphthoic acid, lactone form (Lactone 4), for 3-hydroxymethyl-4-(3-furyl)-7-hydroxy-2-naphthoic acid, lactone form (Lactone 1), the title compound was obtained as a solid; m.p. 221°-222° C.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=O)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:17]([N:24]=[C:25]=[S:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:18]1([CH2:17][N:24]2[C:12](=[O:14])[CH:10]([CH2:9][S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:11][C:25]2=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: S=C=NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1C(CSCc2ccccc2)NC(=S)N1Cc1ccccc1
Yield: 8.9 %

Procedure:
When 2 g of S-benzylcysteine (0.0095 mole), 0.41 g of sodium hydroxide (0.0104 mole) and 1.55 g of benzylisothiocyanate (0.0104 mole) was treated according to the procedure for the preparation of the compound of Example 2, 0.289 g of pure title compound was obtained by crystallization from isopropyl alcohol: 1H NNR was consistent with the assigned structure for the thiohydantoin.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH:12]1([CH3:22])[CH2:17][CH2:16][CH:15]([CH:18]([CH3:20])[CH3:19])[CH:14](O)[CH2:13]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][CH:14]1[CH:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17][CH:12]([CH3:22])[CH2:13]1)=[O:4]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)C(O)c2ccccc2)C1

Procedure:
2.1 kg of hydroxyphenylacetic acid are esterified with 2.5 kg of (-)-menthol in 15 l of boiling toluene with the addition of 40 g of toluenesulphonic acid; the water of reaction is removed from circulation in a water separator. When water is no longer separated, the mixture is cooled, washed with 4 l of saturated NaHCO3 and twice with 4 l of water and concentrated to dryness in vacuo. The title compound is obtained as an oily residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([O:31][CH3:32])[CH:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:44]1[CH:43]=[C:4]([CH:3]=[C:2]([F:1])[CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([O:31][CH3:32])[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)cc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)cc(F)c5)c4)c3c2)ccc1NS(C)(=O)=O
Yield: 53.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(4-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methane sulfonamide (95 mg, 0.14 mmol) was hydrolyzed by lithium hydroxide (18 mg, 0.42 mmol) in THF/methanol/water (2/2/1 ml) to yield 38 mg (52.1% yield) of the titled compound after purification by preparative TLC (Silicagel-1000 micron) using 5% methanol in chloroform as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 11.8 (s, 1H), 8.95 (s, 1H), 8.559-8.552 (d, 1H), 8.42 (s, 1H), 8.367-8.361 (d, 1H), 7.99 (s, 1H), 7.77-7.76 (d, 1H), 7.38 (s, 1H), 7.35-7.32 (m, 2H), 7.20-7.10 (m, 1H), 6.97-6.95 (d, 2H), 5.39 (s, 2H), 3.94 (s, 3H), 2.96 (s, 3H). MS: m/z=510.1 (M+1), HPLC: 87.42% in method B.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:12]=1)[CH3:10]>CN(C)C=O>[ClH:17].[CH2:9]([C:11]1[N:16]=[C:15]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:12]=1)[CH3:10]
Reactant: CCc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Product: CCc1cc(N2CCc3ccccc3C2)nc(N(C)c2ccccc2)n1
Product: Cl
Yield: 57.4 %

Procedure:
After N-methylaniline(0.54 ml, 5.15 mmol) was added to a mixture solution of 6-ethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine(0.7 g, 2.56 mmol) and dimethylformamide(5 ml), 0.56 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12]Cl.[CH3:14][N:15]([CH3:18])[CH:16]=O>>[CH2:10]1[CH2:18][N:15]2[C:14]3[C:5]([CH2:6][CH2:7][CH2:16]2)=[C:4]([OH:8])[CH:3]=[CH:2][C:12]=3[CH2:11]1
Reactant: ClCCCBr
Reactant: CN(C)C=O
Reactant: Nc1cccc(O)c1
Product: Oc1ccc2c3c1CCCN3CCC2
Yield: 62 %

Procedure:
According to a procedure similar to that of Embodiment 1, a mixture of m-aminophenol (5.0 g, 46 mmol), 1 -bromo-3-chloropropane (23.9 g, 15 ml, 151 mmol) and N,N-dimethylformamide (15 ml) was heated and refluxed for 15 hours. After silica gel column chromatography, 8-hydroxyjulolidine (5.5 g) was obtained in 62% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:16][CH2:17][OH:18]>CC(N(C)C)=O>[OH:18][CH2:17][CH2:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=1
Reactant: OCCCl
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccc(C(=O)OCCO)cc1
Temperature: 105 °C
Reaction time: 16 h

Procedure:
17.5 g (0.106 mol) of 4-dimethylamino benzoic acid was dissolved in 80 mL of dimethyl acetamide and added drop wise over 30 minutes to a suspension of 5.32 g (0.133 mol) of sodium hydride (60% in mineral oil) in 50 mL dimethyl acetamide. It became difficult to stir the suspension and an additional 30 mL of dimethyl acetamide was added. 7.2 mL (8.64 g, 0.107 mol) of 2-chloro-ethanol was added and the reaction mixture was heated to 105° C. The reaction was allowed to continue 16 hours at 105° C. The mixture was allowed to cool down to room temperature and the formed sodium chloride was removed by filtration. The solvent was removed under reduced pressure and the residue was crystallized from 400 mL of methanol/water 1/7. The crude 2-hydroxyethyl-(4-dimethylamino benzoate) was isolated by filtration and recrystallized from 200 mL of methanol/water 1/3. 15 g of 2-hydroxyethyl-(4-dimethylamino benzoate) was isolated (m.p. 88-90°).
Reaction SMILES: N([CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)=[N+]=[N-].FC1C(C2N=NC(C)=CC=2)=NC=CC=1.[Cl:32]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCCl>[Cl:32][CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=NCc1ccc(-c2ncccc2F)nn1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: Cc1ccc(-c2ncccc2F)nn1
Solvent: ClCCCl
Product: Fc1cccnc1-c1ccc(CCl)nn1
Temperature: 90 °C

Procedure:
3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine. A solution of 3-(3-fluoropyridin-2-yl)-6-methylpyridazine (200 mg, 1.05 mmol) in 5 mL of DCE was treated with trichloroisocyanuric acid (98 mg, 0.42 mmol). The mixture was heated at 90° C. for 1 h. The mixture was cooled to RT and the precipitate was filtered off with a fritted funnel and rinsed with 2×20 mL of DCM. The brown solid was discarded. The filtrate was washed with 2×5 mL of 0.5 M NaOH (aq.) followed by brine (5 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (55-75% EtOAc in hexanes) to give 3-(chloromethyl)-6-(3-fluoropyridin-2-yl)pyridazine as a brown crystalline solid. MS (ESI, pos. ion) m/z: 224.0 (M+1). A solution of the 3-(chloromethyl)-6-(3-fluoropyridin-2-yl)pyridazine in 1 mL of DMF at RT was treated with NaN3 (69 mg, 1.05 mmol) and stirred at RT for 5 h. The mixture was filtered through a fritted funnel and the collected solid was rinsed with 2×5 mL of EtOAc. The solid was discarded and the filtrate was concentrated and the crude material was purified by silica gel chromatography (35-75% EtOAc in hexanes) to give 3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine (100 mg, 41% yield) as an off white amorphous solid. MS (ESI, pos. ion) m/z: 231.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (1 H, m), 8.27 (1 H, d, J=8.8 Hz), 8.00 (1 H, m), 7.94 (1 H, m), 7.69 (1 H, dt, J=8.4, 4.2 Hz), 4.89 (2 H, s). 19F NMR (376 MHz, DMSO-d6) δ ppm-121.47.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3](Cl)=[O:4].[OH-].[NH4+:15]>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH2:15])=[O:4]
Reactant: CCCCCCCCC(C)C(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Product: CCCCCCCCC(C)C(N)=O
Temperature: 25 °C
Yield: 85.5 %

Procedure:
2-Methyl decanoyl chloride (68.9 g, 336 mmol) was added dropwise to rapidly stirred ammonium hydroxide (200 ml) cooled in an ice bath. The resulting white slurry was stirred at room temperature for one-half hour, then filtered through a Buchner funnel. The filter cake was washed with 100 ml of ice water, air-dried overnight, then dried in a vacuum over at 55° C. for 2 hours to give 53 g (85.5% yield) of a white solid product, m.p. 80°-81° C. (lit. m.p. 81.4° C.).