Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:1]=[O:3])=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: Nc1ccc(Br)cc1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
Formic acid (7 mL, 186 mmol) and acetic anhydride (140.1 mL, 150 mmol) were heated together at 55° C. for 2 hours. The mixture was cooled to room temperature, THF (11 mL) was added followed by 4-bromoaniline (10 g, 58 mmol) in THF (20 mL). The mixture was stirred at room temperature for 3 hours before evaporating to dryness. Trituration of the solid gave the subtitled compound as a light brown solid (8.22 g). MH− 198/200. 1H NMR δ (CDCl3) 6.93-7.04 (2H, d), 7.24 (2H, s), 8.59-8.70 (1H, d).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=[O:11])[CH3:10])[C:3]=1[NH2:4].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:4][C:3]1[C:5]([C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:21]
Reactant: CC(=O)c1cccc(C)c1N
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cccc(C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-6-acetylaniline (25 g) and pyridine (26.5 g) in 1 liter methylene chloride were cooled in an ice-acetone bath. A solution of chloroacetyl chloride (37.9 g) in 100 ml methylene chloride was dripped in slowly. The solution was stirred at room temperature for 2 hours, washed with 10% HCl, 10% NaOH, dried (MgSO4) and stripped. Yield: the title product as a white solid, MP 88°-89° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:3]=1.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C>CC(N(C)C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:4]1[CH:3]=[C:2]([NH:1][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:9]2
Reactant: Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCCCC(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
1-[7-amino-5-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (71 mgs, 0.2 mmoles) was dissolved in anhydrous dimethylacetamide (1 ml) to which was added valeryl chloride (36 ul, 0.3 mmoles) and finally triethylamine (41.6 ul, 0.3 mmoles). The vial was flushed with nitrogen and stirred at room temperature overnight. The product was twice purified by semi-preparative C18 HPLC (11.5 mgs, 13.1% yield, 94% pure, CO-AAW00030).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH:36]1(B(O)O)[CH2:38][CH2:37]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:36]4[CH2:38][CH2:37]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: OB(O)C1CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(C4CC4)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 120 using (1R,2R,4R)-4-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 117) and cyclopropylboronic acid. Light yellow foam. MS (EI): 546.2 (M+H)+.
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:10]=[CH:11][C:12]1[S:13][C:14]2[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[N:21]=1)=O)C.N>CO>[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:10]=[CH:11][C:12]1[S:13][C:14]2[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[N:21]=1
Reactant: CCOC(=O)Oc1cc(C=Cc2nc3c(s2)NCCCC3)ccc1OC
Agent: N
Solvent: CO
Product: COc1ccc(C=Cc2nc3c(s2)NCCCC3)cc1O
Reaction time: 3 h
Yield: 82 %

Procedure:
2-(3-Ethoxycarbonyloxy-4-methoxystyryl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepine (13.2 g) was added to a solution of 1N ammonia in methanol (600 ml), and and the whole was stirred for 3 hrs. at room temperature. The solvent was distilled off under reduced pressure and the residue was purified by a column chromatography on silica gel to give 2-(3-hydroxy-4-methoxystyryl)-5,6,7, 8-tetrahydro-4H-thiazolo [5,4-b]azepine (yield 8.74 g, 81.9%). The product (1.50 g) was converted into its hydrochloride which was recrystallized from a mixture of methanol and ethyl ether to give the title compound (0.49 g, 29.0 %). m.p. 210-211°.
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16](=[O:19])[NH:17][CH:18]=1>CN(C)C=O.O>[CH:1]1([CH2:4][N:17]2[CH:18]=[C:13]([I:12])[CH:14]=[C:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:16]2=[O:19])[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: O=C(Nc1cc(I)c[nH]c1=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(I)cn(CC2CC2)c1=O)OCc1ccccc1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Cyclopropylmethyl bromide (0.100 mL, 0.99 mmol) and cesium carbonate (0.323 mg, 0.99 mmol) were added to a solution of benzyl 5-iodo-2-oxo-1,2-dihydropyridin-3-ylcarbamate (0.245 g, 0.66 mmol) in dimethylformamide (3 mL) and stirred overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 10% to 50% ethyl acetate in hexanes gradient elution) gave the title compound (0.190 g). MS 425 (M+1)
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=[O:17])OC1C=CC([N+]([O-])=O)=CC=1.C(N(CC)CC)C.Cl.[NH:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:19][Si:2]([CH3:1])([CH3:18])[CH2:3][CH2:4][O:5][C:6]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:17]
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCOC(=O)N1CCC(=O)CC1
Yield: 88.3 %

Procedure:
Carbonic acid 4-nitro-phenyl ester-2-trimethylsilanyl-ethyl ester (8.33 g, 29.3 mmol), triethylamine (12.3 g, 122 mmol) and DMAP (3.6 g, 29.5 mmol) were added to a room temperature solution of 4-piperidone hydrochloride (4.52 g, 33.4 mmol) in 100 mL of acetonitrile. The resulting mixture was heated at reflux for 2 h, then cooled and the volatiles were removed in vacuo. The residue was dissolved in dichloromethane, washed with water and 1M NaOH solution, and concentrated in vacuo to leave 6.3 g of product.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH:25]1[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN1CCNCC1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCNCC1CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 95.1 %

Procedure:
A mixture of 7.7 g of 2-chloromethyl-1,4-bis(phenylmethyl)piperazine, 12 g of N-methylpiperazine, 3.5 g of potassium carbonate, 150 ml of dioxane and 60 ml of water was heated overnight at 80°-90° C. and then evaporated. The residual gum was dissolved in dichloromethane, washed with water, dried, filtered and evaporated, giving 8.8 g of 2-[(N-methylpiperazinyl)methyl]-1,4-bis(phenylmethyl)piperazine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: COc1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.496 g, 12.03 mmol) in THF (33.4 mL) at room temperature was treated with 2-fluoro-4-methoxyphenol (1.181 mL, 10.03 mmol) and triphenylphosphine (3.16 g, 12.03 mmol). The reaction mixture was cooled to 0° C. and DEAD (40 wt % in toluene, 5.95 mL, 15.04 mmol) was added dropwise via syringe. The resulting reaction mixture was stirred at 65° C. for 5 h, then at room temperature overnight. Flash silica gel chromatography using a gradient of 10% to 100% EtOAc in hexanes gave tert-butyl 4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 85%) as a light yellow oil. ESI-MS m/z [M+Na]+ 348.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH2:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([CH3:13])[CH:15]=[CH:16]3)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cn1ccc2cc(CN)ccc21
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Product: Cc1cc(Br)ccc1S(=O)(=O)NCc1ccc2c(ccn2C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from 4-bromo-2-methylbenzene-1-sulfonyl chloride and (1-methyl-1H-indol-5-yl)methanamine.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[NH:37]([C:38]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)Nc3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a solution of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dichloromethane (10 ml) is added phenyl isocyanate (0.2 g) under ice-cooling. The mixture is stirred at the same temperature for 30 minutes, and the temperature thereof is raised to room temperature and then the mixture is stirred overnight. The reaction solution is distilled off and the resulting residue is recrystallized from dioxane to give 5-anilinocarbonylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.65 g) as colorless prisms, m.p. 269°-271° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][C:8](Cl)=[N:9][CH:10]=1)=[O:4].[CH3:16][O:17][C:18]([C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)=[O:19].C(N(CC)CC)C>O1CCOCC1>[CH3:16][O:17][C:18]([C@H:20]1[N:25]([C:8]2[N:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=2)[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)=[O:19]
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)OC)nc1C(F)(F)F
Yield: 61 %

Procedure:
Combine 2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (240 mg, 1.70 mmol), (S)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.04 mmol) and triethylamine (5.11 mmol) in a 0.85 M solution of dioxane. Microwave reaction mixture for 30 min at 150° C. Filter reaction mixture and rinse with acetonitrile. Purify filtrate by column chromatography in a 0-70% ethyl acetate/heptane gradient to give (S)-4-(5-Methoxycarbonyl-4-trifluoromethyl-pyrimidin-2-yl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl-ester contaminated with approximately 15% of the mono hydrolysis product. The mixture is carried on to next step without further purification. (61% yield)
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.Cl[Si](C)(C)C.[Cl-].[Mg+2].[Cl-].[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1C(Cl)=O>C1(C)C=CC=CC=1>[CH2:7]([O:6][P:4]([CH2:9][C:10]([C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[F:28])=[O:12])(=[O:5])[O:3][CH2:1][CH3:2])[CH3:8]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(=O)c1ccccc1F)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 2.34 g (11.9 mmol) of diethylphosphonoacetic acid in toluene at 0° C. was added 4.82 g (47.7 mmol) of triethylamine followed by 1.94 g (17.9 mmol) of chlorotrimethylsilane. The mixture was stirred at ambient temperature for 1 hour, then 1.13 g (11.9 mmol) of magnesium chloride was added and the mixture was stirred for a further 1 hour. To the mixture was added 2.0 g (14.3 mmol) of 2-fluorobenzoyl chloride and the mixture was stirred for 72 hours. The mixture was partitioned between 200 ml of water and 250 ml, 100 ml of dichloromethane. The combined organic portions were dried (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography eluting with 3-5% methanol/dichloromethane to give 2.1 g (64%) of [2-(2-fluorophenyl)-2-oxoethyl]phosphonic acid diethyl ester as a colorless oil; MS: m/e 274.9 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[O:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[O:11]1[CH:15]=[CH:14][C:13]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:12]1
Reactant: OB(O)c1ccoc1
Reactant: CC(=O)c1ccc(Br)cn1
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: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccoc2)cn1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)ethanone (0.5 g, 2.5 mmol) in toluene (10 mL) and ethanol (5 mL) was added furan-3-ylboronic acid (0.335 g, 3.0 mmol) and a 2 M solution of aq. Na2CO3. The reaction mixture was degassed with argon, Pd(PPh3)4 (0.144 g, 0.125 mmol) was added, the reaction mixture was degassed with argon for 10 min, and the reaction was heated to 100° C. for 4 h. The reaction mixture was evaporated under vacuum to remove the ethanol, diluted with water (30 mL), extracted with ethyl acetate (100 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage Isolera® One column (using 10% ethyl acetate and hexane) to give 1-(5-(furan-3-yl)pyridin-2-yl)ethanone (0.35 g, 74% yield); 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.44 (s, 1H), 8.20-8.17 (m, 1H); 7.95 (d, 1H), 7.83 (s, 1H), 7.13 (s, 1H), 2.57 (s, 3H): LC-MS m/z calcd for [M+H]+ 187.06. found 188.0.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][C:8](O)=[O:9])(=[O:3])[CH3:2].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:22])=O>CN(C)C=O>[C:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][C:8]([Cl:22])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)CCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OC(C)CCC(=O)Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
46.5 g (0.29 mol) of 4-acetoxypentanoic acid are dissolved at room temperature in 230 ml of abs. toluene, and then 0.2 ml of abs. Dimethyl formamide is added. Then 32.6 ml (0.38 mol) of oxalyl chloride are added dropwise such that the evolution of gas remains under control. When the dropwise addition is complete, the reaction mixture is heated to 50° C. and stirred for 1 hour at this temperature. The orange-red reaction solution is concentrated by evaporation. Distillation of the residue gives 42.2 g of 4-acetoxypentanoic acid chloride as a colorless liquid of b.p.34 110°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22](=O)[CH2:23][CH2:24][C:25]([O:27]C)=O)[CH:19]=3)[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.O.[NH2:31][NH2:32]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22]4[CH2:23][CH2:24][C:25](=[O:27])[NH:31][N:32]=4)[CH:19]=3)[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(OC)cc1)C2
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(S(=O)(=O)NC2Cc3ccc(C4=NNC(=O)CC4)cc3C2)cc1

Procedure:
5.0 g (12 mmol) of methyl 4-(2-p-methoxybenzenesulphonamido-indan-5-yl)-4-oxobutyrate and 3.0 g (60 mmol) of 99% hydrazine hydrate in 25 ml of glacial acetic acid are boiled for 30 minutes. The mixture is evaporated, water is added to the residue, and the reaction product is filtered off with suction and recrystallised from n-propanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(CO)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(CO)cc1

Procedure:
3-(4-Hydroxymethylphenyl)acrylic acid ethyl ester (P4, 3 g, 14.5 mmol) and palladium on charcoal (0.3 g) in ethanol (30 mL) was stirred for 4 hours under atmospheric pressure of hydrogen. The reaction mixture was filtered through celite (Diatomaceous Earth) and concentrated to afford the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.C([O-])([O-])=O.[Na+:36].[Na+].CCCCCCC>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([O-:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.[Na+:36]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCCC
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)[O-])c2)n1
Reaction time: 15 h

Procedure:
A solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [540 mg, 1.17 mmol, Example 49(b)] in MeOH (60 mL) is treated with Na2CO3 (187 mg, 1.78 mmol) and the mixture is stirred for 15 hours. The reaction mixture is filtered and the filtrate is concentrated to dryness. To the residue is added a mixture of methanol, EtOAc and acetone. The insoluble material is filtered off and the filtrate is evaporated. The residue is again treated with a mixture of methanol, EtOAc and acetone, the insoluble material filtered off and the filtrate is evaporated. The residue is again treated with a mixture of methanol, EtOAc and acetone, the insoluble material filtered off and the filtrate is evaporated. To the residue is added MeOH (1 mL) and EtOAc (5 mL), followed by heptane until the solution turned cloudy and a solid is formed slowly. Heptane is repeatedly added until the solution stay clear. The mixture is filtered affording sodium 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionate as a crystalline. LC/MS: RT=2.34 minutes, MS: 460 (M-Na+ 2H)+. 1H NMR [300 MHz, (CD3)2SO]: □ 7.97 (1H, br s), 7.24-7.7 (7H, m), 6.57 (1H, s), 3.86 (3H, s), 3.58 (2H, m), 2.98 (2H, m), 1.4 (6H, s).
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](Cl)=O.B(F)(F)F.CCOCC>O1CCOCC1>[CH3:11][O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:10][N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: COC(=O)c1ccccc1C(=O)Cl
Reactant: NC(=NO)c1ccccc1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1ccccc1-c1nc(-c2ccccc2)no1

Procedure:
A solution of 13.6 g. (0.1 mole) benzamide oxime in 625 milliliters dioxane is treated dropwise with 19.8 g. (0.1 mole) 2-chloroformyl benzoic acid methyl ester in 200 milliliters dioxane. This mixture is then refluxed for one hour, cooled slightly and treated with 3.3 milliliters of boron trifluoride etherate. The reaction mixture is refluxed for 18 hours. The resulting residue is cooled and filtered to remove a small amount of solid. The filtrate is evaporated in vacuo and the resulting oil is dissolved in ether, washed with water, 10 percent sodium carbonate, water and then brine. The ether solution is dried over anhydrous magnesium sulfate decolorized with charcoal filtered to remove the charcoal and the filtrate evaporated in vacuo to give o-(3-phenyl-1,2,4-oxadiazol-5-yl)-benzoic acid methyl ester.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f4) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.