Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.Cl.[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:13][CH2:12][N:11]([CH3:15])[CH3:10])[N:7]=1
Reactant: CN(C)CCCl
Reactant: O=c1ccc(Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C)CCn1nc(Cl)ccc1=O
Temperature: 65 °C
Yield: 22.5 %

Procedure:
To a solution of 6-chloro-2H-pyridazin-3-one (500 mg, 3.83 mmol) in 5 mL dimethylformamide was added 2-dimethylaminoethyl chloride hydrochloride (828 mg, 5.75 mmol), potassium carbonate (1.59 g, 11.5 mmol) and sodium iodide (632 mg, 4.21 mmol). The mixture was stirred over night at 65° C. Solvent was evaporated. The crude product was dissolved in water and purified by preparative HPLC using a gradient of acetonitrile/5% acetonitrile—water phase containing 0.1 M ammonium acetate, to give 174 mg of 6-chloro-2-(2-dimethylamino-ethyl)-2H-pyridazin-3-one as light brown crystals after freeze drying (22% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:14][CH:13]=1)#[N:2].Cl[Sn]Cl.O>C(O)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:14][CH:13]=2)[CH:5]=1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2cc([N+](=O)[O-])ccc2C#N)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2cc(N)ccc2C#N)cc1
Temperature: 90 °C
Yield: 82 %

Procedure:
Prepare propane-2-sulfonic acid [2-(2′-cyano-5′-nitro-biphenyl-4-yl)-thiophen-3-yl]-amide in a manner analogous to the procedure set forth in Preparation 4. Add SnCl2.2 H2O (642 mg, 3.40 mmol) into a solution of propane-2-sulfonic acid [2-(2′-cyano-5′-nitro-biphenyl-4-yl)-thiophen-3-yl]-amide (279 mg, 0.654 mmol) in ethanol (6.54 mL). Heat the mixture at 90° C. for 3 h. Cool to room temperature. Concentrate to remove the solvent in vacuo. Dilute with dichloromethane, and add aqueous sodium bicarbonate solution to adjust pH to 8. Extract with with dichloromethane (3×100 mL) and dry the combined organic layers and concentrate to give a slightly colored solid. Purification by flash chromatography (Silica gel-Hexane/EtOAc 2:1) furnishes 212 mg, 0.534 mmol (82%) of title compound as a pale yellow solid. MS (m/e): 396.1 (M−1).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([O-:13])=[O:12]>CN1C(=O)CCC1.C(OCC)(=O)C>[N+:11]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Nc2nc3ccccc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
A mixture of 2-chlorobenzimidazole (10.0 g) and 4-nitroaniline (9.05 g) in NMP (130 mL) was stirred at 120° C. for 3 days. After this time, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (750 mL) and washed with water (750 mL). The aqueous layer was extracted with ethyl acetate (750 mL) and the combined organic extracts were washed with water (3×750 mL) then brine (750 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was triturated with 1:1 ethyl acetate/heptane (200 mL) and the solid that formed was collected by filtration to afford N-(4-nitrophenyl)-1H-benzimidazol-2-amine (4.00 g) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[H][H]>C1COCC1.[Ni]>[NH2:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[SH:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Br)ccc1S
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(Br)ccc1S

Procedure:
The mixture of 4-bromo-2-nitro-benzenethiol and its disulfide from Example 2A (14.9 g, 53.5 mmol) in THF (450 mL) was mixed with Raney Ni (30 g, 100% wt). The mixture was hydrogenated in a 1000 mL Paar shaker at a hydrogen pressure of 40 psi at 50° C. for 41 hours. When the reaction was complete, the solids were filtered. The solid filter-cake was dissolved in pyridine (600 mL) at 100° C. and filtered to remove the Ni residue. This pyridine solution contained mostly the 2-amino-4-bromophenyldisulfide. Crude yield=11.9 g (92%)
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)C.O>[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCOc1ccc(C=O)cc1
Reactant: O=C1CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCOc1ccc(C=C2Cc3ccccc3C2=O)cc1
Reaction time: 0.33 h

Procedure:
1-Indanone (4.17 g, 0.032 mol) was dissolved in ethanol (20 ml), and was added to sodium hydroxide (0.44 g, 0.011 mol) dissolved in water (8 ml) and ethanol (3 ml) and was left to stir for 20 min. 4-(Hexyloxy)benzaldehyde (6.4 ml, 0.031 mol), dissolved in ethanol (35 ml), was added to the mixture and was stirred for 4 hours. The product was isolated by vacuum filtration and was washed with cold ethanol (2×20 ml) and was dried in a vacuum oven. Yield=8.47 g, 85%. 1H NMR and 13C NMR gave expected signals.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].Cl.[OH-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:12]([F:17])[F:16])[C:3]=1[F:10]
Reactant: Oc1c(Cl)ccc(Br)c1F
Reactant: O=C([O-])C(F)(F)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1c(Br)ccc(Cl)c1OC(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-6-chloro-2-fluorophenol (1.00 g, 4.44 mmol) and sodium chlorodifluoroacetate in dimethylformamide (DMF; 9 mL) was added potassium carbonate (1.22 g, 5.32 mmol) and water (1.77 mL) and the resulting mixture heated to 100° C. for 4 hours. The solution was cooled to ambient temperature and concentrated hydrochloric acid (2.5 mL) and water (4 mL) were added and stirred at ambient temperature overnight. The solution was cooled in an ice bath and neutralized with 2N sodium hydroxide and then extracted with ethyl ether (2×25 mL). The combined extracts were washed with brine, dried (sodium sulfate), and concentrated to give 1-bromo-4-chloro-2-fluoro-3-difluoromethoxybenzene (1.20 g, 4.2 mmol). This material was used without further purification.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:19])[CH3:18]
Reactant: NC1CC1
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
A mixture of cyclopropylamine (1.39 g, 24.3 mmol) and triethylamine (3.5 g, 35 mmol) was added drop-wise to a 0° C. solution of ethyl chloro(oxo)acetate (3.5 g, 26 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at 0° C. for 10 minutes and filtered; the filtrate was concentrated in vacuo to afford the product as a yellow solid Yield: 3.0 g, 19 mmol, 78%. 1H NMR (400 MHz, CDCl3) δ 7.14 (br s, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.78-2.86 (m, 1H), 1.38 (t, J=7.2 Hz, 3H), 0.83-0.90 (m, 2H), 0.59-0.65 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[ClH:19].[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][S:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2nc1S
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc2ccccc2nc1SCc1ccccc1N(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
In a mixture of 50 ml of acetone and 5 ml of water were suspended 2.80 g of 2-mercapto-3-methylquinoxaline, 3.28 g of 2-dimethylaminobenzyl chloride hydrochloride, and 8.0 g of potassium carbonate. The resulting mixture was stirred at room temperature for 40 min., and the solvent was removed under reduced pressure. The residue was extracted with chloroform after addition of chloroform and water. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residue was diluted with 50 ml of ethanol. To the solution under chilling with ice were successively added 1.33 ml of conc. hydrochloric acid and ether to precipitate crystals. The crystals were collected by filtration to give 4.56 g of 2-(2-dimethylaminobenzylthio)-3-methylquinoxaline hydrochloride as a dark brown crystalline powder.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24](B4OC(C)(C)C(C)(C)O4)=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:36]([CH3:38])[CH3:37])[CH3:15])=[CH:8][C:7]=1[CH3:39].C([O-])([O-])=O.[Na+].[Na+].Br[C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:36]([C:17]1[N:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:48]3[N:53]=[CH:52][CH:51]=[CH:50][N:49]=3)=[CH:25][CH:26]=2)[O:20][C:16]=1[CH:14]([CH3:15])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[C:7]([CH3:39])[CH:8]=1)([CH3:37])[CH3:38]
Reactant: Brc1ncccn1
Reactant: COC(=O)CCc1ccc(OCC(C)c2oc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2C(C)C)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(OCC(C)c2oc(-c3ccc(-c4ncccn4)cc3)nc2C(C)C)ccc1CCC(=O)O
Temperature: 90 °C

Procedure:
A solution of 3-[4-(2-{4-isopropyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-5-yl}-propoxy)-2-methyl-phenyl]-propionic acid methyl ester (91 mg, 0.166 mmol) in toluene (4.0 mL) is bubbled with nitrogen gas for 10 minutes. To this, Pd(dppf)Cl2 (10 mg), Na2CO3 (1.0 mL, 2.0 M), 2-bromopyrimidine (53 mg, 0.333 mmol) are added. The resulting suspension is stirred and heated at 90° C. for 48 hours. It is then concentrated, purified on silica gel chromatography column with 20–40% EtOAc/Hexanes to yield the pyrimidine intermediate.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([OH:16])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][C:28]=1[CH2:29]Br.O>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([O:16][CH2:29][C:28]1[CH:31]=[C:32]([O:35][C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:34][C:27]=1[O:26][CH3:25])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Reactant: COc1ccc(OC(F)(F)F)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1CO[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Reaction time: 0.17 h

Procedure:
(1R*,2R*,5R*)-8-Benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 348 mg, 1.19 mmol) was dissolved in THF then sodium hydride (71 mg, 60% in oil, 1.79 mmol) added and the reaction mixture stirred for 10 minutes. 2-methoxy-5-trifluoromethoxybenzyl bromide was added and the reaction mixture stirred at 50° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [5%-15% ethyl acetate in iso-hexane] to give the title compound. (205 mg, 35%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH3:38])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CNS(=O)(=O)c1cccc(N)c1
Product: CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-methyl-benzenesulfonamide [CAS 459434-40-3] according to general procedure II. Yellow solid. MS (ISP) 542.0 [(M−H)−]; mp 232° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[CH:7]1)[CH2:3][OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[CH:7]1)[CH:3]=[O:4]
Reactant: CC(C)(CO)Cn1cnc(-c2cccnc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C=O)Cn1cnc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propanol (11 mg) in CH2Cl2 was added Dess-Martin periodinane (41 mg) and the resulting solution was stirred at room temperature for 15 minutes. Saturated NaHCO3 was added, the aqueous layer was extracted with CHCl3, the combined organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuo to afford the title compound as a slightly yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:15])[O:13][CH3:14])[CH3:10])=[CH:4][CH:3]=1.C=O.S(=O)(=O)(O)O.[C:23](O)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH:9]([CH3:10])[N:11]([C:12]([O:13][CH3:14])=[O:15])[CH2:23]2)=[CH:6][CH:7]=1
Reactant: COC(=O)NC(C)Cc1ccc(Br)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: O=S(=O)(O)O
Product: COC(=O)N1Cc2cc(Br)ccc2CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a mixture of methyl [2-(4-bromophenyl)-1-methylethyl]carbamate (465 mg, 1.71 mmol) and paraformaldehyde (82.1 mg, 2.73 mmol) was added a mixture of concentrated sulfuric acid (2.5 mL, 47 mmol) and glacial acetic acid (3.75 mL, 66.0 mmol). The resulting mixture was stirred at r.t. overnight. The reaction mixture was poured into ice-water, and extracted with CH2Cl2. The organic layer was washed with water, saturated NaCO3 aqueous solution and brine, dried with MgSO4. After filtration, the filtrate was concentrated to afford the desired compound (490 mg, 100%) which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=284.2.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:24])([C:10]2[CH:15]=[CH:14][C:13]([O:16]CC3C=CC=CC=3)=[CH:12][CH:11]=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25]>CO.O1CCCC1.[Pd]>[ClH:25].[C:1]1([CH2:7][C:8]([NH2:24])([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)(Cc1ccccc1)c1ccc(O)cc1
Reaction time: 6 h

Procedure:
To a solution of 1-phenyl-2-[4-(phenylmethoxy) phenyl)-2-propylamine (3.50 g, 0.011 mol) in methanol (100 mL), tetrahydrofuran (50 mL) and 1N hydrochloric acid (20 mL) was added 5% palladium on carbon (0.8 g) and themixture was shaken on a Parr apparatus at approximately 40 psi for 6 h. Thecatalyst was removed by filtration and the solvent removed under vacuum. Crystallization from 2-propanol and ether and vacuum drying at 80° C. for 48 h provided 1.3 g of 1-phenyl-2-(4-hydroxyphenyl)-2-propylamine hydrochloride; mp 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([NH:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CNC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)NCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a solution of ethyl N-{3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoyl}glycinate (D125) (150 mg) in THF (15 mL) was added aqueous NaOH (2 M, 2 mL). The reaction was stirred at 20° C. for 3 h. The mixture was acidified with aqueous HCl (2 M) to pH 5-6, partitioned between ethyl acetate (50 mL) and water (25 mL). The organic phase was dried over sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford N-{3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoyl}glycine (E77) (120 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.56 (2H, t), 2.99 (2H, t), 3.76 (2H, d), 4.89 (1H, m), 7.21 (1H, t), 7.27 (1H, s), 7.44 (1H, d), 7.82 (1H, d), 7.93 (1H, d), 8.20 (2H, m), 8.37 (1H, d), 10.78 (1H, s), 12.46 (1H, s). MS (ES): C24H23ClN4O6 requires 482; found 483.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][O:7][C:8]([NH:10][C@H:11]([C:20](OC)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:9].O.O.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>C(O)C.N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:20][OH:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:9]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccc(OC)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)N[C@H](CO)Cc2ccc(O)cc2)cc1OC
Temperature: 25 °C
Yield: 62.9 %

Procedure:
In a mixture of 80 ml of ethanol and 30 ml of pyridine, 6.54 g of methyl N-(3,4-dimethoxybenzyloxycarbonyl)-tyrosinate was dissolved. To the solution, 4.41 g of calcium chloride dihydrate was added. Then, to the mixture, 2.27 g of sodium borohydride was slowly added while stirring at room temperature. The resulting mixture was stirred for 3 hours and neutralized with 3% hydrochloric acid. After addition of 250 ml of water, the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 3.82 g of N-(3,4-dimethoxy-benzyloxycarbonyl)-tyrosinol. The crystals were recrystallized from ethanol to give small needles with mp. 152°-155° C. Analysis, calculated for C19H23NO6 : C, 63.14; H, 6.42; N, 3.88; found C, 63.30; H, 6.29; N, 3.99.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12.C(N(CC)CC)C.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[CH:13]([OH:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1ncc2c(Cl)c3c(nc21)C(O)c1ccccc1CC3
Reaction time: 6 h

Procedure:
20.2 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.065 mol.) and 13 g. of triethylamine (0.13 mol.), dissolved in 400 ml. of ethyl acetate and 75 ml. of absolute ethanol, are catalytically hydrogenated in the presence of 2 g. of palladium on charcoal (10%) at room temperature. In about 6 hours, the theoretical amount of hydrogen is absorbed. The catalyst is then filtered off, the filtrate evaporated in vacuo and the residue extracted with 200 ml. of ether. The ethereal extract is washed with water, dried with Na2SO4 and the ether removed. The resulting material is recrystallized from petroleum ether (60°-70°) to yield 12.7 g. (62.5%) of 4-chloro-1-ethyl-1,5,6,11-tetrahydro[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ol; m.p. 128°-130°.
Reaction SMILES: CN[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH3:19]NC(C1C=C(Cl)C=CN=1)=O>CCOC(C)=O>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3](=[O:4])[CH3:19])[CH:10]=2)=[CH:17][CH:16]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 1-(4-chloropyridin-2-yl)ethanone for 4-chloropyridine-2-carboxylic acid methylamide. 1H-NMR (Acetone-d6) δ 8.53 (d, J=5.4 Hz, 1H), 7.36 (d, J=2.7 Hz, 1H), 7.08 (dd, J=5.4, 2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 6.77 (d, J=9.0 Hz, 2H), 4.77 (br s, 2H), 2.59 (s, 3H); LC MS m/z 229 (M+H)+, RT=1.11 min; TLC (50% EtOAc/Hex), Rf=0.30.
Reaction SMILES: [F-].[K+].[NH2:3][C:4]1[C:9]([F:10])=[C:8](Cl)[N:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:5]=1[CH:16]=[CH2:17].CC1(C)C(C)(C)OB([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)O1.C(#N)C>C(Cl)Cl.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[N:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:5]=1[CH:16]=[CH2:17]
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: C=Cc1c(C(=O)OC)nc(Cl)c(F)c1N
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(C#N)cc2)c(F)c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 5-mL microwave safe vial was added potassium fluoride (0.227 g, 3.90 mmol), methyl 4-amino-6-chloro-5-fluoro-3-vinylpicolinate (0.3 g, 1.301 mmol), bis(triphenylphosphine)palladium (II) chloride (0.091 g, 0.130 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.313 g, 1.366 mmol. A mixture of water (1 mL) and acetonitrile (2 mL) was added and the reaction was capped and placed in a Biotage Initiator™ microwave reactor for 20 min at 115° C., with external IR-sensor temperature monitoring from the side of the vessel. Upon cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (25 mL) and water (25 mL) and the organic layer was filtered through cotton plug. An additional extraction using EtOAc (25 mL) was combined with the CH2Cl2 and dried over of Na2SO4 (50 g). Following filtration of the combined organics through a cotton plug and concentration on a rotary evaporator, the residue was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as a tan solid (297 mg).