Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.COCCOC.C(=O)([O-])[O-].[K+].[K+]>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>[C:22]1([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(-c3ccccc3)nc2)CC1

Procedure:
1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (0.89 g, 2.5 mmol), phenyl boronic acid (0.37 g, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.12 mmol), 1.2-dimethoxyethane (50 ml), potassium carbonate (1.0 g, 7.5 mmol) and water (7.5 ml) was stirred at reflux overnight. Water (50 ml) was added and the mixture was extracted twice with ethyl acetate (40 ml). Chromatography on silica gel with a mixture of petroleum: ethyl acetate (1:1) gave the title compound as an oil. Yield 0.83 g. 94%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([NH:19][NH:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1>P(Cl)(Cl)(Cl)=O>[F:28][C:24]1[CH:23]=[C:22]([C:21]2[O:18][C:17](/[CH:16]=[CH:15]/[C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:19][N:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)c2cccc(F)c2)ccc1-n1cnc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(/C=C/c2nnc(-c3cccc(F)c3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of 3-fluorobenzoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (86 mg) in phosphorus oxychloride (2 mL) was stirred at 120° C. for one hour. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Methylene chloride and a 1 N sodium hydroxide solution were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 65 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1/[CH:23]=[CH:24]/[CH3:25])([C:11]([OH:13])=[O:12])[CH2:5]2.[CH3:27]CO>[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[CH2:23][CH:24]([CH3:27])[CH3:25])([C:11]([OH:13])=[O:12])[CH2:5]2
Reactant: CCO
Reactant: C/C=C/c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(F)cc2C1
Agent: [Pd]
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(F)cc3C2)c1CC(C)C
Temperature: 25 °C
Yield: 78 %

Procedure:
5-Fluoro-2-[3-methyl-2-((E)-propenyl)-benzoylamino]-indan-2-carboxylic acid (154) (270 mg, 0.76 mmol) is dissolved in absolute EtOH (15 mL) by heating. The resulting solution is cooled down to RT under argon and then is added the catalyst, Pd—C (5 wt. % Pd, 125 mg, 5.9% mmol). The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 50 psi, 50° C., overnight. The catalyst is removed by filtration through a pre-column (10 g silica gel) and washed with EtOH. The combined organic solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (155) as white solid (210 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B(O)O)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[CH3:29][C:30]1[C:34]2[CH:35]=[C:36]([OH:39])[CH:37]=[CH:38][C:33]=2[O:32][N:31]=1>>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C@H:16]1[C:15]2[CH:24]=[CH:25][C:12]([O:11][C@H:9]3[C:10]4[C:6](=[C:5]([O:39][C:36]5[CH:37]=[CH:38][C:33]6[O:32][N:31]=[C:30]([CH3:29])[C:34]=6[CH:35]=5)[CH:4]=[CH:3][C:2]=4[F:1])[CH2:7][CH2:8]3)=[CH:13][C:14]=2[O:18][CH2:17]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B(O)O)ccc(F)c43)ccc21
Reactant: Cc1noc2ccc(O)cc12
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6onc(C)c6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from (R)-7-fluoro-1-[(S)-3-methoxycarbonylmethyl-2,3-dihydrobenzofuran-6-yloxy]-2,3-dihydro-1H-inden-4-ylboronic acid and 3-methyl-benzo[d]isoxazol-5-ol following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.68 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C=O)C>[CH2:37]([O:36][C:34]([N:6]1[C:5]([C:20]2[N:24]([C:25]3[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=3)[N:23]=[CH:22][CH:21]=2)=[C:4]([CH3:3])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]1=[O:19])=[O:35])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)n1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
Sodium hydride (38 mg of a 60% dispersion in mineral oil, 0.95 mmol) was added to a solution of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (300 mg, 0.73 mmol) in DMF under a nitrogen atmosphere. The mixture was stirred for 5 minutes and the resultant yellow solution was treated with ethyl chloroformate (104 mg, 0.091 mL, 0.95 mmol). The mixture was stirred for 1 h then treated with water and extracted with EtOAc. The organic phase was washed with water and brine then dried (sodium sulfate) and concentrated in vacuo. The residue was purified by chromatography using silica gel eluting with 25%-50% ethyl acetate in cyclohexane. The product thus obtained was freeze-dried from acetonitrile-water to afford the title compound (194 mg) a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][N:5]([C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(CCN1CCOCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
A solution of N-tert-butoxycarbonyl glycine methyl ester (9.4 mL, 63.6 mmol) in DMF (250 mL) was cooled in an ice bath and treated with NaH (60% dispersion in mineral oil, 2.85 g, 71.2 mmol). After stirring at 0° C. under N2 for 30 min and then at room temperature for 30 min, the mixture was cooled in an ice bath and treated with a solution of 4-(2-chloroethyl)morpholine (10.5 g, 70 mmol) in DMF (50 mL). After stirring at 0° C. for 30 min, the mixture was stirred at room temperature overnight. The mixture was diluted with H2O (600 mL) and then extracted with EtOAc (5×300 mL). The combined organic layers were washed with H2O (4×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2) gave the title compound (0.79 g, 4%) as a colorless oil: MS (ESI) m/e 303 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.[NH2:22][C@H:23]([C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[CH3:24].[BH3-]C#N.[Na+]>C(O)C>[CH2:14]([O:13][C:11]([CH:10]([NH:22][C@H:23]([C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[CH3:24])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)C(=O)CCc1ccc(Cl)cc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(CCc1ccc(Cl)cc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
A solution of ethyl 4-p-chlorophenyl-2-oxobutyrate (prepared from the acid by esterification with ethanol in refluxing CCl4) and L-alanyl-L-proline in ethanol can be treated with excess NaBH3CN and stirred at room temperature until reaction is complete. The ethanol can then be removed under vacuum and the product absorbed on strong acid ion-exchange resin. By elution with 2% pyridine in water, one can obtain N-(1-ethoxycarbonyl-3-p-chlorophenylpropyl)-L-alanyl-L-proline.
Reaction SMILES: Cl[C:2]1[C:7](CCC(O)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>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>[C:13]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CCc1cccnc1Cl
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2ccccn2)cc1
Temperature: 100 °C
Yield: 91 %

Procedure:
Pd(PPh3)4 (3.0 g, 2.6 mmol) was added to a solution of 2-chloro-3-carboxyethylpyridine (25 g, 134.7 mmol), phenylboronic acid (21.04 g, 172.6 mmol) and K2CO3 (55.1 g, 399 mmol) in 1,4-dioxane (200 mL) and water (200 mL). The reaction mixture was heated at 100° C. for 2 h. The solution was then cooled to room temperature and the dioxane was removed under reduced pressure. The resulting aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (Na2SO4), filtered through celite, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10-100% EtOAc/hexanes) to get the 2-phenylpyridine derivative in 91% yield (27.98 g). LC-MS Rt (retention time): 2.45 min, MS: (ES) m/z 228 (M+H+).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:34]=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](=[O:33])[C:25]([NH:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])=[O:26])=[CH:16]2)=[CH:11][CH:10]=1)#[N:4]>CCO.C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]([CH:34]=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]([OH:33])[C:25]([NH:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])=[O:26])=[CH:16]2)=[CH:13][CH:14]=1)#[N:4]
Reactant: N#Cc1cc(Oc2ccc(-n3cc(C(=O)C(=O)NC[C@H](O)CO)c4ccccc43)cc2)ccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc(Oc2ccc(-n3cc(C(O)C(=O)NC[C@H](O)CO)c4ccccc43)cc2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
NaBH4 (20 mg) was added to a solution of compound 68 (50 mg) in EtOH/THF (2 mL/2 mL) at room temperature, and the mixture was shaken at room temperature for 1 hour. The reaction was quenched with water, extracted with EtOAc (30 mL), concentrated, and purified by column (CHCl3/MeOH 10/1.5) to give compound 69 as a white solid (40 mg, 40%): 1H-NMR (400 MHz, CD3OD): δ 7.72-7.76 (m, 2H), 7.49-7.53 (m, 2H), 7.3-7.46 (m, 4H), 7.05-7.21 (m, 4H), 5.35-5.37 (m, 1H), 3.67-3.73 (m, 1H), 3.43-3.47 (m, 3H), 3.28-3.32 (m, 1H); LC/MS: m/z=548.2 [M+Na]+ (Calc: 525.4).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:19]([O:22][CH2:23][C:24](Cl)=[O:25])(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:25])(=[O:21])[CH3:20]
Reactant: COc1cccc(N)c1C(N)=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(NC(=O)COC(C)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-6-methoxybenzamide (1.7 g) in methylene chloride (20 ml) is added pyridine (1.6 ml), and thereto is added dropwise acetoxyacetyl chloride (1.1 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 2 hours, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and then are recrystallized from ethanol to give the title compound (2.1 g) having the following physical properties.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.CCCCCC>C1COCC1>[CH2:14]([O:13][C:11]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[C:4]([CH2:3][OH:2])[CH:12]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1cc(C(=O)O)cc(C(=O)OC)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCOc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
A solution of 5-Butoxy-isophthalic acid monomethyl ester (1.0 g, 4.0 mmol) in THF (20 mL) is treated with 2.0 M borane-dimethyl sulfide complex in hexane (10 mL, 20 mmol). The mixture is stirred at room temperature for 48 h. The mixture is quenched carefully with methanol (10 mL) and is concentrated to dryness. The residue is purified by flash chromatography to afford the title compound as a solid (0.78 g, 88%). LC-ES/MS m/e 211.3 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12](=[O:16])[NH:13][C:14]=1[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C)C=O>[C:1]([C:9]1[CH:10]=[CH:11][C:12](=[O:16])[NH:13][C:14]=1[CH:15]=[CH:19][N:20]([CH3:22])[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1[nH]c(=O)ccc1C(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CN(C)C=Cc1[nH]c(=O)ccc1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture containing 26.5 g of 5benzoyl-6-methyl-2(1H)-pyridinone, 100 ml of dimethylformamide and 21 ml of dimethylformamide dimethyl acetal was heated on a steam bath with stirring for 8 hours and then concentrated on a rotary evaporator to yield a solid residue. The residue was recrystallized from methanol and dried in a vacuum oven at 80°-85° C., to yield 15.8 g of 5-benzoyl-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinone, m.p. 202°-204° C.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][C:4]=1[N+:16]([O-])=O)#[N:2]>[OH-].[NH4+]>[NH2:16][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:3]=1[C:1]#[N:2])[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: N#Cc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Product: N#Cc1ccc(C(=O)CCC(=O)O)cc1N

Procedure:
A solution of 3-(4-cyano-3-nitrobenzoyl)propionic acid in 5N ammonium hydroxide solution was added to a well stirred boiling aqueous solution of ferrous sulphate. The pH was adjusted to 9 with concentrated ammonium hydroxide solution and the mixture was refluxed for 15 minutes. The filtrate was concentrated and neutralised with glacial acetic acid to give 3-(3-amino-4-cyanobenzoyl)propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:7]([CH3:18])[CH:6]=1)=[O:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:7]([CH2:18][Br:37])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a solution of 191 mg (0.73 mmol) of 4′-chloro-2-methyl-biphenyl-4-carboxylic acid methyl ester in 4 mL of carbon tetrachloride (CCl4) was added 9.7 mg (0.04 mmol) of benzoyl peroxide, followed by 124 mg (0.696 mmol) of N-bromosuccinimide (NBS), and the reaction mixture was heated at reflux for 6 h. The mixture was cooled to rt, diluted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give 132 mg (53%) of 2-bromomethyl-4′-chloro-biphenyl-4-carboxylic acid methyl ester, as an oil, which was used without any further purification in the next step. 1H NMR δ CDCl3 8.10 (s, 1H), 7.91–7.89 (d, J=8.0 Hz, 1H), 7.37–7.35 (d, J=8.3 Hz, 2H), 7.30–7.18 (d, J=8.7 Hz, 2H), 7.22–7.20 (d, J=8.0 Hz, 1H), 4.30 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[C:7]([OH:19])[CH:6]=1)(=[O:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].IC>C(C(C)=O)C>[C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[C:7]([O:19][CH3:20])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(O)c(C(=O)CCCCCl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)CCCCCl
Yield: 67.7 %

Procedure:
1-(4-Acetylamino-5-chloro-2-hydroxyphenyl)-5-chloropentan-1-one (1.07 g, 3.5 mmol), potassium carbonate (1.38 g, 10.0 mmol) and iodomethane (0.62 mL, 10.0 mmol) were combined in methyl ethyl ketone (20 mL) and stirred at reflux temperature for 4 hours, 15 minutes. The mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed in brine, dried over sodium sulfate, and then evaporated to leave a solid residue. Crystallization of the residue from ethyl acetate-hexanes gave 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloro-pentan-1-one (0.720 g, 2.37 mmol), m.p. 98°-100° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1([F:29])[C:12](=[O:13])[C:11]2[N:7]([C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[C:9]3[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH3:21])[C:10]3=2)[CH2:6][CH2:5]1>CO.O1CCCC1>[F:29][C:4]1([F:3])[CH:12]([OH:13])[C:11]2[N:7]([C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[C:9]3[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH3:21])[C:10]3=2)[CH2:6][CH2:5]1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(=O)C(F)(F)CC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(O)C(F)(F)CC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (7.2 mg, 0.19 mmol) was added to solution of 9,9-difluoro-5-(3-fluorophenyl)-1,3-dimethyl-8,9-dihydropyrimido[4,5-a]indolizine-2,4,10(1H,3H,7H)-trione (55 mg, 0.15 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) at 0° C. The mixture was stirred at room temperature for 30 mins. The reaction was quenched with water (10 mL) and extracted with DCM (6×5 mL). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum to afford the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:16]=[C:15]4[CH:34]=O)[C:9]([CH3:36])=[C:8]([F:37])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=3)[CH:16]=[C:15]4[CH2:34][N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[C:9]([CH3:36])=[C:8]([F:37])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)cc(CN3CCN(C)CC3)c2c1

Procedure:
The title compound was prepared by the method of Example 59 step iv) using product of example 112 step i) and 1-methyl-piperazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7](O)[CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C1COCC1>[Br:32][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:8][CH2:9][CH3:10]
Reactant: BrC(Br)(Br)Br
Reactant: CCCC(O)c1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Br)c1ccccn1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a mixture of 1-(pyridin-2-yl)butan-1-ol (0.35 g, 2.3 mmol; Example 231, Step A) and triphenylphosphine (1.1 g, 4.2 mmol) in THF (15 mL) at 0° C. under N2 atmosphere was added CBr4 (1.2 g, 3.5 mmol). The mixture was stirred at 0° C. for 2 min, and then was allowed to warm to rt and stirred for 25 min. The precipitate was filtered off through a pad of Celite® (J.T. Baker, Phillipsberg, N.J., diatomaceous earth), the solid was washed with cold THF (10 mL). The filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel with 0-5-15% EtOAc/Hexanes provided the title compound as colorless oil. Mass Spectrum (ESI) m/z=214.0 and 216.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].Cl>C(OCC)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[CH:2][C:7]=1[Si:17]([CH3:19])([CH3:18])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(Br)c([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dibromoanisole (13.3 g, 50 mmol) in diethyl ether (50 ml) at 0° C. was added over 20 min 1.5M butyllithium (33.4 ml) and the reaction was allowed to react 15 min at 0° C. Then trimethylsilylchloride (5.43 g, 50 mmol) in diethyl ether (20 ml) was added over 10 min and the resulting mixture was stirred 18 hours at room temperature. At 0° C. 3N HCl (50 ml) was added and the organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. 4-Bromo-3-trimethylsilylanisole was purified by chromatography on silica gel (eluted with cyclohexane) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34]CC)=[O:33]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[CH2:23][CH:22]2[CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Product: O=C(O)CC1CC2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate followed by a procedure analogous to that in Example 2. LC-MS Method 1 tR=1.93, min, m/z=482, 480