Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.C(N(CC)CC)C.[Cl-].[C:23]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:24][C:25]([O-])=[O:26].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([C:25](=[O:26])[CH2:24][C:23]([O:29][CH2:30][CH3:31])=[O:28])[CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(C)Nc1cc(Br)ccc1C(=O)O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N(c1cc(Br)ccc1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 4-bromo-2-(propan-2-ylamino)benzoic acid (6.8 g, 26.64 mmol) in 260 mL of DCM is added triethylamine (4 mL, 31.6 mmol), followed by dropwise addition of ethyl malonate chloride (4.0 mL, 31. mmol). The mixture is stirred for 2 hours at room temperature, and then poured into molar hydrochloric acid solution and extracted with EtOAc. The organic phase is washed with water and with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated to dryness. 7.15 g of a pale yellow solid are obtained (yield: 72%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:24][C:23]1[CH:25]=[CH:26][C:20]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:11])=[CH:21][CH:22]=1
Reactant: O=C1NCc2c(Br)cccc21
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: COCCOC
Solvent: O
Product: Nc1ccc(-c2cccc3c2CNC3=O)cc1
Temperature: 90 °C
Reaction time: 19 h
Yield: 59.1 %

Procedure:
A suspension of Example 1C (2 g, 9.43 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)aniline (2.5 g, 11.3 mmol), and Na2CO3 (2.2 g, 20.8 mmol) in DME (68 mL) and water (17 mL) was purged with nitrogen, treated with Pd(PPh3)4 (1 g, 0.9 mmol), and stirred at 90° C. for 19 hours. The reaction mixture was cooled to room temperature, concentrated to one-third its original volume, diluted with ethyl acetate (30 mL) and water (20 mL), and filtered. The filter cake was washed with water and ethyl acetate and dried to give 1.25 g of the desired product. MS (ESI(+)) m/e 225 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.C([NH:8][C:9]1[C:17]([Cl:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)(=O)C.[NH2:21][CH:22]1[CH2:26][N:25]([CH2:27][CH3:28])[N:24]([CH2:29][CH3:30])[CH2:23]1>>[NH2:8][C:9]1[C:17]([Cl:18])=[CH:16][C:12]([C:13]([NH:21][CH:22]2[CH2:26][N:25]([CH2:27][CH3:28])[N:24]([CH2:29][CH3:30])[CH2:23]2)=[O:15])=[C:11]([O:19][CH3:20])[CH:10]=1
Reactant: CCN1CC(N)CN1CC
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCN1CC(NC(=O)c2cc(Cl)c(N)cc2OC)CN1CC

Procedure:
The title compound was prepared as described in Example 6 of U.S. Pat. No. 4,207,327 from 4-acetamido-5-chloro-2-methoxy-benzoic acid thionyl chloride and 4-amino-1,2-diethylpyrazolidine, m.p. 117°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][O:17]S(C)(=O)=O)=[CH:12][C:11]([Cl:22])=[CH:10][C:8]=2[N:9]=1.[CH3:27][O-].[Na+].CO.[Na]>O>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][O:17][CH3:27])=[CH:12][C:11]([Cl:22])=[CH:10][C:8]=2[N:9]=1
Reactant: CS(=O)(=O)OCCCc1cc(Cl)cc2nc(Cc3ccccc3Cl)oc12
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COCCCc1cc(Cl)cc2nc(Cc3ccccc3Cl)oc12

Procedure:
2-(2-Chlorobenzyl)-5-chloro-7-(3-methanesulfonyloxy-1-propyl)-benzoxazole was stirred overnight with a solution of sodium methoxide prepared from methanol (100 ml) and sodium (2.7 g, 0.118 mol). The reaction mixture was diluted with water and extracted with dichloromethane. The dichloromethane solution was washed with water and evaporated to give the crude product (10 g). The crude product was purified over flash chromatography silica gel and eluted with 30% dichloromethane/hexane. The effluent was collected in 200 ml fractions. Fractions 1-7 contained an impurity (7.1 g); fractions 8-11 were collected (1.8 g) and recrystallized three times from hexane to give the title compound (0.4 g), mp 49-51°.
Reaction SMILES: CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[Cl-].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C@H:31]2[CH2:35][CH2:34][CH2:33][NH2+:32]2)=[O:30])=[CH:24][CH:23]=1.[O:36]=[C:37]1[CH2:42][O:41][CH2:40][CH2:39][N:38]1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][C:50](O)=[O:51])=[CH:45][CH:44]=1>CN(C=O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]([C@H:31]2[CH2:35][CH2:34][CH2:33][N:32]2[C:50](=[O:51])[CH2:49][C:46]2[CH:45]=[CH:44][C:43]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][C:37]3=[O:36])=[CH:48][CH:47]=2)=[O:30])=[CH:26][CH:27]=1
Reactant: O=C(O)Cc1ccc(N2CCOCC2=O)cc1
Reactant: O=C(Nc1ccc(Cl)cc1)[C@H]1CCC[NH2+]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)[C@H]1CCCN1C(=O)Cc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.26 ml (2.4 mmol) of 4-methylmorpholine and 230 mg (1.2 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 261 mg (1.00 mmol) of (R)-2-(4-chlorophenylcarbamoyl)pyrrolidinium chloride and 235 mg (1.00 mmol) of 4-(3-oxomorpholin-4-yl)phenylacetic acid in 2 ml of DMF, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is introduced into water, and the precipitate formed is filtered off, giving N-(4-chlorophenyl)-(R)-1-{2-[4-(3-oxomorpholin-4-yl)phenyl]acetyl}pyrrolidine-2-carboxamide as a slightly brownish solid; ESI 442.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])=[O:5].[I-].[K+].Br[CH2:17][CH2:18][C:19]#[CH:20]>CN(C)C=O>[CH3:13][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])([CH2:20][CH2:19][C:18]#[CH:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#CCCBr
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCCC(C)(C(=O)OCC)S(C)(=O)=O
Reaction time: 3 h
Yield: 34.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.9 g, 17.2 mmol, 1.2 equiv) was added to a solution of ethyl 2-(methylsulfonyl)propanoate (14.8 g, 82.0 mmol, 1.0 equiv) in N,N-dimethylformamide (180 mL) at room temperature. After the evolution of gas subsided (approx. 30 min), a stirred mixture of potassium iodide (2.89 g, 17.2 mmol, 0.2 equiv) and 4-bromobut-1-yne (10.9 g, 82.0 mmol, 1.0 equiv) in N,N-dimethylformamide (20 mL) was added dropwise via cannula (approx. 2 h). After 3 h, the reaction was quenched with water (200 mL), and the resulting solution was extracted with 1:1 ethyl acetate-hexanes (2×200 mL). The combined organic phases were washed with water (2×50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (340 g silica gel column, 0-25% gradient ethyl acetate in hexanes) to provide the title compound as a clear colorless oil (6.63 g, 35%). MS (GCMS) m/z 233 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ1.33 (t, J=7.12 Hz, 3H) 1.64 (s, 3H) 2.00 (t, J=2.63 Hz, 1H) 2.11-2.22 (m, 1H) 2.22-2.32 (m, 1H) 2.33-2.45 (m, 1H) 2.46-2.58 (m, 1H) 3.05 (s, 3H) 4.28 (q, J=7.16 Hz, 2H).
Reaction SMILES: C[O:2][P:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:4][CH3:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[CH2:19]Cl)([CH3:15])([CH3:14])[CH3:13]>>[CH3:5][O:4][P:3]([CH2:19][C:18]1[CH:17]=[C:16]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:23]([OH:24])=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: COP(OC)c1ccccc1
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Product: COP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1ccccc1
Temperature: 110 °C
Yield: 82.9 %

Procedure:
A mixture of 5 grams (29 mmol) of dimethylphenylphosphonite with 7.5 grams (29 mmol) of 3,5-di-tert-butyl-4-hydroxybenzyl chloride (CAS REG #955-01-1) is heated at 110° C. for 1 hour and cooled to obtain a white solid. The resultant solid is crystallized from 100 mL of hexane to give 9 grams (83% yield) of (3,5-di-tert-butyl-4-hydroxy-benzyl)-phenyl-phosphinic acid methyl ester as a white solid mp 112-114° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:25])[C:14](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[CH2:15][CH3:16])[CH3:11]>>[CH2:10]([O:12][C:13](=[O:25])[C:14](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:19]=1)[CH2:15][CH3:16])[CH3:11]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCOC(=O)C(=Cc1cccc(N)c1)CC
Product: CCOC(=O)C(=Cc1cccc(NC(=O)c2ccc(Br)o2)c1)CC

Procedure:
5-Bromo-furan-2-carboxylic acid (88 mg, 0.46 mmol) was coupled to 2-(3-amino-benzylidene)-butyric acid ethyl ester (100 mg, 0.46 mmol) using Method C to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:6])[CH2:4][CH3:5].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1>CN(C=O)C>[Si:11]([O:6][C@@H:3]([CH2:4][CH3:5])[CH2:2][NH2:1])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC[C@H](O)CN
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H](CN)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the product from step (ii) (310 mg) in DMF (10 mL), tert-butylchlorodimethylsilane (734 mg) was added followed by imidazole (474 mg) and stirred at rt for 24 h. The mixture was washed with water and extracted with EtOAc, dried and the solvent removed to give the subtitle compound as a yellow oil, 610 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([O-:27])=[O:26])[CH2:10][CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:13][N+:14]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO>[C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([O:27][CH2:12][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:26])[CH2:10][CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CCC(C[N+](=O)[O-])c1cccc(Cl)c1Cl)C(=O)[O-]
Reactant: [H][H]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CCC(CN)c1cccc(Cl)c1Cl)C(=O)OCc1ccccc1
Yield: 182.1 %

Procedure:
To an EtOH rinsed (4×5 mL) slurry of Raney Ni (1 mL) was added a solution of benzyl (5R or S)—N,N-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-6-nitro-D-norleucinate (0.52 g, 0.85 mmol) in EtOH (5 mL). This slurry was hydrogenated under a balloon of hydrogen for 2 h. The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (0.45 g). MS 581 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[N:25][CH:26]=3)[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[N:25][C:24]([N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[CH:23][CH:22]=3)[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3noc([C@H](CCCC4CCCCC4)CC(=O)NO)n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(-c2ccc(N3CCNCC3)nc2)no1)NO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9.7 %

Procedure:
To a solution of the title compound from Example 32 (0.37 g, 0.7 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the reaction was stirred at room temperature for 1.5 hours. The solvent was removed in vacuo and the residue was azeotroped with toluene. The residue was then dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution (30 mL) followed by 10% aqueous citric acid solution (30 mL). The acidic aqueous layer was basified to pH 7 with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (30 mL), dried (MgSO4) and the solvent was removed in vacuo to give the title compound as a viscous oil (0.03 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][NH:6][NH2:7])[CH3:2].CO[C:13](=[CH2:16])[C:14]#[N:15].C(OCC)(=O)C>O>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][N:6]1[C:14]([NH2:15])=[CH:13][CH:16]=[N:7]1)[CH3:2]
Reactant: CCOC(CNN)OCC
Reactant: C=C(C#N)OC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(Cn1nccc1N)OCC
Yield: 19.3 %

Procedure:
A mixture of hydrazinoacetaldehyde diethyl acetal (21 g) and methoxyacrylonitrile (11.8 g) in water (150 ml) was refluxed for 2 days. After the reaction mixture was cooled, to the mixture was added a mixture of water and ethyl acetate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and evaporated to give 1-(2,2-diethoxyethyl)-5-aminopyrazole (5.45 g).
Reaction SMILES: I[C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C[Sn](C)(C)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>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.O1CCOCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: C[Sn](C)(C)c1ccccn1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1-c1ccccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
In a 25 mL pear shaped flask was placed 5-iodo-2'-deoxycytidine (0.425 g, 1.2 mmol), 2-trimethylstannylpyridine (1.4 g, 5.8 mmol), Bis (triphenylphosphine)-palladium (II) chloride (0.084 g, 0.12 mmol), and anhydrous 1,4-dioxane (15 mL). The reaction was heated at 60° C. for 15 hrs then at 90° C. for 1 h. The solvent was evaporated and the residue purified by silica gel chromatography (10% CH3OH in CH2Cl2 (1% NH3)) to yield 0.173 g (47%) of the title compound as a white solid m.p. 197°-198° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:25][OH:26])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(C(CO)c1ccccc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1

Procedure:
Dissolve 0.40 g (0.9 m mole) of 8-chloro-11-[1-(2-hydroxy-1-phenylethylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine (Example 41 of Table 2) in 10 mL of pyridine and stir under nitrogen. Add 0.15 g (1.3 m mole) of methanesulfonyl chloride and stir for 20 hours. Concentrate under vacuo and triturate the residue with ether. Purify the resulting solid by silica gel chromatography using 2% MeOH saturated with amonia, and 98% CH2Cl2 as the solvent. The product is obtained as a white solid, mp=110.7-111.6° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11]1([C:17](=O)[C:18]([O:20]CC)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[O:10]=[C:2]1[C:3](=[C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([OH:20])=[O:19])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)C(=O)c1ccccc1
Product: O=C(O)C(=C1C(=O)Nc2ccccc21)c1ccccc1
Yield: 25.1 %

Procedure:
Oxindole (390 mg, 3mmol) was condensed with ethyl phenylglyoxylate (540 mg) using method A to give 200 mg (25%) of the title compound as a yellow solid.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:40])[C@H:11]([N:15]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[S:16]([C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH3:27])=[C:21]([CH3:28])[C:20]=1[CH3:29])(=[O:18])=[O:17])[C@@H:12]([OH:14])[CH3:13])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[OH:8][NH:9][C:10](=[O:40])[C@H:11]([N:15]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[S:16]([C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH3:27])=[C:21]([CH3:28])[C:20]=1[CH3:29])(=[O:18])=[O:17])[C@@H:12]([OH:14])[CH3:13]
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)NOCc2ccccc2)[C@H](C)O)c(C)c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)NO)[C@H](C)O)c(C)c1C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-hydroxybutyramide (1.25 g, 2.19 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran (100 mL) was added 10% Pd—C (0.7 g), and the resulting mixture was hydrogenated at atmospheric pressure for 60 min. The reaction mixture was degassed under argon and the slurry was filtered over Celite. The Celite cake was washed with ample 80% ethanol-methylene chloride and the filtrate was concentrated to almost dryness. The mixture was dissolved in 4 mL of ethyl acetate which was added slowly dropwise to 100 mL of vigorously stirring hexanes. The slurry was filtered to afford N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3(S)-hydroxybutyramide (0.67 g) as a white solid.
Reaction SMILES: C(OC([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])[CH:9]=[CH:10][CH:11]=1)=O)C.[CH2:19]([O:21][C:22](C1C=CC=CC=1OB(C1C=CC=CC=1)O)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:7]1[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[CH:9][CH:10]=[CH:11][CH:6]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1ccccc1OB(O)c1ccccc1
Reactant: CCOC(=O)c1cccc(-c2ccccc2Br)c1
Product: CCOC(=O)c1ccccc1-c1ccccc1Br

Procedure:
Prepared using the same conditions for the synthesis of 2′-bromo-biphenyl-3-carboxylic acid ethyl ester substituting 3-ethoxycarbonylphenyl boronic acid with 2-ethoxycarbonylphenylphenyl boronic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[NH:21][N:20]=1>>[O:11]=[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:21]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=3[C:19]([C:18]([F:17])([F:29])[F:28])=[N:20]2)=[CH:3][CH:4]=1
Reactant: O=C(CCc1ccc(Br)cc1)N1CCCC1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Product: O=C(CCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1

Procedure:
The title compound was prepared from 1-[3-(4-bromophenyl)propanoyl]pyrrolidine and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 19.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1(C)C=CC=CC=1.Cl[C:19]1[C:24]([Cl:25])=[N:23][CH:22]=[CH:21][N:20]=1.[C:26]([O:29][CH2:30][CH3:31])(=[O:28])[CH3:27]>[Cl-].[NH4+]>[Cl:25][C:24]1[C:19]([CH2:27][C:26]([O:29][CH2:30][CH3:31])=[O:28])=[N:20][CH:21]=[CH:22][N:23]=1
Reactant: CCOC(C)=O
Reactant: Clc1nccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1nccnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.8 %

Procedure:
To a 1.0 M solution of LiHMDS in toluene (14.8 mL, 14.8 mmol) under nitrogen at 0° C. was added 2,3-dichloropyrazine (0.699 mL, 6.71 mmol) and ethyl acetate (0.725 mL, 7.38 mmol). The mixture was stirred overnight for 18 hours, allowing the ice bath to warm to room temperature. The mixture was poured into saturated ammonium chloride (100 mL), and extracted with diethyl ether (3×100 mL). The combined ether extracts were washed with brine, dried (sodium sulphate) and evaporated. The residue was chromatographed (40 g silica cartridge, 0-25% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I99) (0.414 g, 31% yield) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=2.5 Hz, 1H), 8.31 (d, J=2.5 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.03 (s, 2H), 1.27 (t, J=7.1 Hz, 3H). LCMS Method C: rt 5.16 min.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:2]([CH3:4])[CH3:3].[CH3:17][O:18]C(Cl)Cl.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[C:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:8]=1)=[O:18]
Reactant: COC(Cl)Cl
Reactant: COC(=O)Cc1ccccc1OCC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1cc(C=O)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 10 ml of methylene chloride is dissolved 1.00 g of methyl 2-(2-isobutoxyphenyl)acetate. After successively adding 0.99 ml of titanium tetrachloride and 0.45 ml of α,α-dichloromethyl methyl ether at 5-10° C., the mixture thus obtained is stirred at ambient temperature for 30 minutes. The reaction mixture is added to a mixture of methylene chloride and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5) to obtain 0.80 g of methyl 2-(5-formyl-2-isobutoxyphenyl)acetate as a colorless oily product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CN(CCCN)c1ccccn1
Reactant: CSc1ncc(Cc2ccc(Cl)c(Cl)c2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2ccc(Cl)c(Cl)c2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (0.66 g) and 2-methylthio-5-(3,4-dichlorobenzyl)pyrimid-4-one (1.0 g) were heated together under reflux in pyridine (2.5 ml) for 24 hr. After stripping, the residue was recrystallised three times from ethanol/water to give 2-[3-(N-methyl-N-pyrid-2-ylamino)propylamino]-5-(3,4-dichlorobenzyl)pyrimid-4-one 0.25H2O, 1.0 g (70%) mp 104°-6° C.