Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43].[Cl-].[NH4+]>C(Cl)Cl>[C:42]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])(=[O:44])[CH3:43]
Reactant: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
141 mg (0.30 mmol) of (−)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-1a-1)) was dissolved in 6 ml of methylene chloride, followed by the addition of 29 μl (0.36 mmol) of pyridine and 24 μl (0.33 mmol) of acetyl chloride under 0° C. The reaction mixture was stirred at room temperature for 1 hour. To the reaction solution, 10 ml of saturated aqueous solution of ammonium chloride was added and extracted with 50 ml of methylene chloride. The extract was washed with 20 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:4 mixture of ethyl acetate and hexane) to obtain 155 mg of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Product: O=C(O)C=Cc1ccc(C(F)(F)F)cc1F

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3h20) between 2-fluoro-4-(trifluoromethyl)benzaldehyde (5.000 g; 26.027 mmol) and malonic acid (5.145 g; 49.451 mmol) gave the product 3-(2-fluoro-4-trifluoromethyl-phenyl)-acrylic acid as a colorless solid (5.030 g; 82.5%). LC-MS: tR=0.89 min; [M+H]+: no ionisation.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1Br.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:9][C:5]1[CH:4]=[C:3]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:8]
Reactant: Nc1ccccc1
Reactant: Cc1cc(Br)c(Br)cc1C
Product: Cc1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C
Yield: 92.9 %

Procedure:
The synthesis is carried out in accordance with the general procedure in accordance with Example 2 from 63.3 g (240 mmol) of 1,2-dibromo-4,5-dimethylbenzene and 46 ml (505 mmol) of aniline. The precipitated solid is recrystallised from toluene/acetonitrile (5:1), and the residue is washed with MeOH, giving 65 g (223 mmol) of a crystalline solid. The overall yield is 93%.
Reaction SMILES: C([N:3](C([O-])=O)[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O=[S:25](Cl)Cl>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:4]=[N:3][S:25][C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: CCN(N=C(Cc1ccccc1)c1ccc(OC)cc1)C(=O)[O-]
Reactant: O=S(Cl)Cl
Product: COc1ccc(-c2nnsc2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
The acylhydrazine 12 (23.4 g, 75.0 mmol) was added to SOCl2 (200 ml) at 0° C. The reaction was warmed to 60° C. and complete (by TLC) after 3 hours. SOCl2 was removed under reduced pressure. The solid residue was dissolved in EtOAc, washed once with 10% aqueous NaOH and brine. The organic layer was dried over MgSO4, and the solvent was removed under reduced pressure. The crude solid was recrystallized from Et2O to afford 10 (13.0 g, 64.6%), m.p. 81.5°-82.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]([O:14]C)=[O:13])[N:4]=1.[OH-].[Na+]>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[N:6]=1
Reactant: COC(=O)Cc1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)nc(CC(=O)O)n1
Temperature: 25 °C

Procedure:
20 g of methyl (4,6-dimethoxypyrimidin-2-yl)acetate are stirred for 2 hours at 50° C. with 3.9 g of sodium hydroxide in 300 ml of water. The mixture is cooled to room temperature and extracted three times using diethyl ether, and the aqueous phase is acidified to pH 2 using 2 N hydrochloric acid and extracted four times using 150 ml portions of ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is distilled off, and the residue is dried in vacuo. This gives 13.1 g of (4,6-dimethoxypyrimidin-2-yl)acetic acid of melting point 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[CH:16][C:3]=12.[I:17]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([I:17])[C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1c(-c2ccccc2)nnc2[nH]ncc12
Solvent: CC#N
Product: Clc1c(-c2ccccc2)nnc2[nH]nc(I)c12

Procedure:
A suspension of 4-chloro-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (2.44 g, 10.6 mmol) and N-iodosuccinimide (3.58 g, 15.9 mmol) in acetonitrile (106 mL) was heated at reflux for 1 d. The yellow solid was collected by filtration whilst warm to provide a mixture of the title compound and starting material (9:1, 4 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:16][C:6]2[N:7]([CH3:15])[C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH3:23][N:24]=[C:25]=[O:26]>O1CCCC1>[CH3:23][NH:24][C:25](=[O:26])[O:14][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:15])[C:6]3[CH2:16][CH:3]([CH2:2][OH:1])[CH2:4][C:5]=3[C:13]=2[CH:12]=1
Reactant: CN=C=O
Reactant: Cn1c2c(c3cc(O)ccc31)CC(CO)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)CC(CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-2-hydroxymethyl-4-methylcyclopent[b]indol-7-ol (1.7 g, 0.008 mole) in 50 ml of tetrahydrofuran was added milled K2CO3 (2.0 g, 0.015 mole), followed by a solution of methylisocyanate (0.5 ml, 0.008 mole) in 5 ml of tetrahydrofuran. After stirring at ambient temperature for two hours, the mixture was filtered and the filtrate concentrated to a yellow solid. This material was eluted on a silica gel column with ethyl acetate/dichloromethane (1:2) via HPLC. The desired fractions were combined and concentrated to a white solid, 2.1 g, m.p. 134°-8° C. This material was recrystallized from methanol/ether (1:10) to give the product as a white solid, 1.5 g, m.p. 137°-8° C.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2][CH3:3].[C:13]1([C:19]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:20]2[C:24]([C:25]3[C:30]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=4)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:23][N:22]=[N:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CCOC(C)=O>[CH2:1]([C:4]1[N:12]([CH2:37][C:34]2[CH:33]=[CH:32][C:31]([C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[N:20]([C:19]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:21]=[N:22][N:23]=3)=[CH:36][CH:35]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ncccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCc1nc2cccnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
2-propyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)-biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Example 7, Part A from 2-propylimidazo[4,5-b]pyridine (19 mg, 0.118 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (60 mg, 0.108 mmol), and NaH (0.236 mmol). Yield: 18 mg (26%) thick oil; Rf: 0.75 (SiO2 tic, 100% EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.27 (dd, 1H, J=6, 1 Hz), 8.01 (dd, 1H, J=9, 1 Hz), 7.85 (dd, 1H, J=9, 1.5 Hz), 7.50-7.42 (m, 2H), 7.38-7.22 (m, 11H), 7.08 (d, 2H J=7 Hz), 6.98-6.88 (m, 7H), 5.40 (s, 2H), 2.66 (t, 2H, J=7.5 Hz), 1.80-1.65 (m, 2H), 0.93 (t, 3H, J=6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[CH:17]([CH3:25])[C:18]([N:20]1[CH2:24][CH2:23][CH2:22][O:21]1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:17]([CH3:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][O:21]3)=[O:19])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(Cl)C(=O)N1CCCO1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)N1CCCO1
Reaction time: 5 h
Yield: 95.9 %

Procedure:
A mixture of 4-(4-chlorophenoxy)phenol (22.1 g), N-[(±)-2-chloropropionyl]isoxazolidine (16.4 g) which was prepared as in Example 1, anhydrous potassium carbonate (15.2 g) and acetonitrile (300 ml) was heated under reflux with stirring for 5 hours. After cooling, the reaction mixture was filtered through a suction filter to remove solid matters and the filtrate was concentrated in vacuo. The residue was washed with the addition of water and benzene and the organic layer formed was separated and dried over anhydrous sodium sulfate. The removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(4-chlorophenoxy)phenoxy]propionyl]isoxazolidine (33.4 g) as a pale yellow crystalline solid. Recrystallization from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 98°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2[nH]ccc2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 5-amino-indole (Aldrich) according to the method described in Example 1c. Melting Point: 80-82° C. (ethyl acetate)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:21]3([CH2:26][CH2:25][O:24][C:23]([NH2:27])=[N:22]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=3)[O:14][C:11]2=[N:12][CH:13]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCOCC1.O>[Br:7][C:8]1[CH:9]=[C:10]2[C:21]3([CH2:26][CH2:25][O:24][C:23]([NH2:27])=[N:22]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:35]4[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:19]=3)[O:14][C:11]2=[N:12][CH:13]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Temperature: 85 °C

Procedure:
In a 150-mL resealable flask, potassium carbonate (1.557 g, 11.27 mmol 3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (intermediate 25 1.97 g, 4.17 mmol), 2-fluoropyridin-3-ylboronic acid (0.441 g, 3.13 mmol), and PdCl2-dppf-dcm (0.225 g, 0.275 mmol) were suspended in dioxane (18 mL) and water (6 mL). Argon was blown through the vessel, which was sealed and heated in an 85° C. oil bath for 2 h. The reaction was concentrated to remove most of the dioxane. The aqueous residue was diluted further with dilute brine (50 mL), and the aqueous phase was extracted with 10% MeOH-DCM (3×100 mL). The organics were combined, washed with dilute brine (30 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (4% MeOH/DCM), to afford (3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) (1.03 g). MS (m/z) 441/443 (M+H)+. Step 2: Intermediates ((S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) (intermediate 26A, 350 mg), and its enantiomer ((R)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (intermediate 26 B, 500 mg) were obtained from racemic (3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) using similar chiral separation conditions as described herein for intermediate 10. MS (m/z) 441/443 (M+H)+.
Reaction SMILES: O1CCCC1.[CH3:6][C@@:7]12[C:13](=O)[CH2:12][C@@H:11]1[CH2:10][CH:9]=[CH:8]2.CP([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(C)=O.[H-].[Na+]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:6][C@@:7]12[C:13](=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][C@@H:11]1[CH2:10][CH:9]=[CH:8]2
Reactant: C[C@]12C=CC[C@H]1CC2=O
Reactant: CC(C)(C)OC(=O)CP(C)(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1C[C@@H]2CC=C[C@]12C

Procedure:
An anhydrous tetrahydrofuran solution (2 mL) of (±)-(1S,5R)-5-methylbicyclo[3.2.0]hept-3-en-6-one (800 mg, 6.55 mmol) was added dropwise with stirring under ice cooling to a reaction solution prepared in advance from an anhydrous tetrahydrofuran solution (10 mL) of tert-butyl dimethylphosphorylacetate (1.28 g, 6.55 mmol) and sodium hydride (>63% oil, 245 mg, 6.55 mmol), and the mixture was then stirred for 1 hour in this bath and further stirred at room temperature for 2 hours. The reaction solution was diluted with an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (389 mg).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[NH:14][N:13]=1>C1COCC1.CCOC(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>[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cc2ccc(Cl)cc2)c2ccccc12

Procedure:
A solution of (4-chlorobenzyl)zinc(II) chloride in THF was added to a suspension of 4-chlorophthalazin-1(2H)-one and Pd(PPh3)4 in THF, and subjected to microwave conditions at 180° C. for 20 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated to give crude 4-(4-chlorobenzyl)phthalazin-1(2H)-one. This material was treated with O-(diphenylphosphoryl)hydroxylamine similar to that described in Example 1B to give the title compound. LC/MS (APCI) M/Z 286 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:38]2[CH:50]=[CH:49][C:41]([CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:40][CH:39]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:38]2[CH:39]=[CH:40][C:41]([CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:49][CH:50]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 55 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.065 g, 55%). LCMS: 559.35 (M+1)+; HPLC % 99.26 (@254 nm) (Rt; 3.983; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.15 (t, 1H), 7.58 (d, 2H, J=8 Hz), 7.36 (d, 3H, J=8.4 Hz), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.84 (d, 2H, J=11.2 Hz), 3.57 (m, 3H), 3.48 (m, 3H), 3.24 (m, 2H), 3.40 (m, 1H), 2.63 (s, 3H), 2.36 (m, 4H), 2.23 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.60 (m, 4H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:30]([NH:32][NH2:33])=O)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)CCC>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2([C:30]3[N:13]4[CH2:14][CH2:15][S:16][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([CH3:19])[CH2:11][C:12]4=[N:33][N:32]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: NNC(=O)C1(c2ccc(Br)cc2)CC1
Reactant: CSC1=NCCSC(C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CCCCO
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A solution of 7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-methyl-5-(methylthio)-2,3,6,7-tetrahydro-1,4-thiazepine (34.4 g, 108 mmol) and the compound (27.5 g, 108 mmol) obtained in Example 16-3) in 1-butanol (800 mL) was stirred at 140° C. for 6 h. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1 to 1:0) to obtain the title compound (36.3 g, 66%) as a white solid.
Reaction SMILES: O=[C:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[Cl:23][C:24]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:25]=1[NH2:26]>C1C=CC=CC=1>[Cl:23][C:24]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:25]=1[NH:26][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(=O)C(=O)OCc1cccc(Oc2ccccc2)c1
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Solvent: c1ccccc1
Product: CC(C)[C@H](Nc1c(Cl)cc(Cl)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of m-phenoxybenzyl 2-oxo-3-methylbutanoate, 0.39 g of 2,4,6-trichloroaniline, 0.02 g of p-toluenesulfanylacetate and 10 ml of benzene is heated to reflux for about 5.5 hr. A Dean-Stark trap is used to remove water. The reaction is worked by pouring into ether/sodium bicarbonate solution. The organic phase is washed with water and brine, dried over magnesium sulfate and evaporated. To the reaction product (0.79 g) is added 3 ml of methanol, 1 ml of THF and 0.19 g of NaCNBH3. The reaction mixture is stirred at RT and then adjusted to pH 3 to 4 with concentrated sulfuric acid. Stirring at RT is continued overnight. The reaction is worked up as before using ether/sodium bicarbonate solution and subjected to prep. TLC eluting with 20% ether/hexane to yield the m-phenoxybenzyl ester of N-(2,4,6-trichlorophenyl)valine, MS m/e 477 (M+).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1.O>CCOCC>[F:3][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([Br:1])[C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: BrBr
Reactant: O=C1CCCCc2ccc(F)cc21
Solvent: O
Solvent: CCOCC
Product: O=C1c2cc(F)ccc2CCCC1Br
Reaction time: 1 h
Yield: 101.3 %

Procedure:
68.9 g of bromine are added dropwise to a solution of 73.1 g of 3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one in 700 ml of ether under ice-cooling during 1 hour. After the mixture is stirred for 1 hour, the reaction mixture is poured into water and the mixture is extracted with ether. The ether layer is washed, dried and evaporated to remove the solvent to obtain 106.8 g of 3-fluoro-6-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one as an oil.
Reaction SMILES: C([O:4][C@H:5]1[C@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@H:15]([CH3:26])[O:14][CH:6]1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[S:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C@H:6]1[O:14][C@@H:15]([CH3:26])[C@@H:16]([OH:22])[C@@H:17]([OH:18])[C@@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(Sc2ccccc2)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 232.7 %

Procedure:
To a solution of phenyl 6-deoxy-2,3,4-tri-O-acetyl-1-thio-β-L-galactopyranoside 2 (0.892 g, 2.33 mmol) in 25 mL of methanol is added K2CO3 (0.644 g, 4.66 mmol). The reaction mixture is stirred at room temperature for 12 h. Amberlite resin (H+ form) is added to the reaction mixture and stirred for an additional 30 min. The neutralized mixture is then filtered through Celite, which is washed several times with methanol, and the filtrate is concentrated to afford 1.39 g of phenyl 6-deoxy-1-thio-β-L-galactopyranoside 3 as a yellow oil, which is used in the next step without further purification. The thioglycoside 3 can be purified using flash chromatography (10% MeOH/CH2Cl2): Rf 0.28 (10% MeOH/CH2Cl2); 1H NMR (C6D6, 270 MHz) δ 7.54-7.58 (m, 2H) 7.28-7.37 (m, 3H), 4.50 (d, J=8.2 Hz, 1H, H-1), 3.70 (q, J=6.6 Hz, 1H, H-5), 3.56-3.75 (m, 3H), 1.38 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH3:10])[CH:4]=1.C1OCCOCCOCCOCCOCCOC1.[C-:29]#[N:30].[K+].ClCCl>C(#N)C>[CH3:10][S:9][C:5]1[CH:4]=[C:3]([CH2:2][C:29]#[N:30])[CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: CSc1cccc(CCl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CSc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
To a solution of 1-chloromethyl-3-methylsulfanyl-benzene (26.9 g, 0.156 mol) and 18-crown-6 (2 g, 7.8 mmol) in dry acetonitrile (100 mL) was added potassium cyanide and stirred at room temperature for 48 hours. A precipitate was formed while adding dichloromethane (400 mL). The suspension was filtered, washed with water (2×150 mL), dried (Na2SO4) concentrated and distilled under reduced pressure to give a colorless oil (22.9 g, 91%). MS: 161.9 (M+1−).