Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[O:36][CH2:35][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14](C(C4C=CC=CC=4)C4C=CC=CC=4)[C:13]3=[O:34])[C:4]=2[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C(OCC)(=O)C.[H][H]>CO.[Pd]>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2([C:4]3[C:5]4[O:10][CH2:9][CH2:8][O:7][C:6]=4[CH:11]=[CH:2][C:3]=3[O:36][CH2:35]2)[C:13]1=[O:34]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1Nc2ccccc2C12COc1ccc3c(c12)OCCO3
Temperature: 60 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
6-chloro-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one (2.1 g, 4.24 mmol) was suspended in methanol (20 mL) and ethyl acetate (80 mL) in a steel bomb and palladium on carbon (20% w/w, 0.45 g) was added. The bomb was pressurized with hydrogen gas (120 psi) and the mixture was stirred at 60° C. for 16 h. The reaction mixture was allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue triturated with ethyl acetate to afford 2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one (0.522 g, 42%) as a colorless solid: mp 259-261° C.; 1H NMR (300 MHz, CD3OD) δ7.27-7.18 (m, 1H), 7.09-6.88 (m, 3H), 6.70 (d, J=8.7 Hz, 1H), 6.39 (d, J=8.7 Hz, 1H), 4.75 (d, J=9.3 Hz, 1H), 4.59 (d, J=9.0 Hz, 1H), 4.12-3.90 (m, 4H); 13C NMR (75 MHz, CD3OD) δ 181.0, 157.5, 142.4, 141.3, 139.6, 133.9, 129.8, 124.5, 124.0, 119.0, 117.1, 111.0, 102.9, 82.4, 66.0, 65.2, 59.1; MS (ES+) m/z 296.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH:19]=O)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.C([BH3-])#N.[Na+].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(C=O)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1c2ncc(CNc3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
The 2-chloro-5,11-dihydro-11-ethyl-8-formyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.50 g, 0.16 mmol) was dissolved/suspended in methanol (2 mL) and treated with sodium cyanoborohydride (0.030 g, 0.47 mmol) followed by aniline (0.043 mL, 4.7 mmol). The mixture was stirred for 5 minutes then acetic acid (0.020 mL, 0.35 mmol) was added. After an additional 3 hours at room temperature the mixture was made alkaline with 15% sodium hydroxide and the white suspension was extracted with dichloromethane (3×10 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography then chromatotron (hexane to 1:1 hexanes/ethyl acetate gradient) to give the title compound (0.031 g, 50%), m.p. 79°-80° C.
Reaction SMILES: [OH:1][C:2]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[C:16]([OH:23])=[C:15]([CH3:24])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([S:13][CH3:14])=[S:12])[CH2:7][CH2:6]1.Cl.CO>O>[CH3:22][O:21][C:17]1[C:16](=[O:23])[C:15]([CH3:24])=[C:3]([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([C:11]([S:13][CH3:14])=[S:12])[CH2:9][CH2:10]2)[C:2](=[O:1])[C:18]=1[O:19][CH3:20]
Reactant: COc1c(O)c(C)c(CN2CCN(C(=S)SC)CC2)c(O)c1OC
Agent: Cl
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CN2CCN(C(=S)SC)CC2)=C(C)C1=O
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To 700 mg (1.88 mmol.) of methyl 4-(2,5-dihydroxy-3,4-dimethoxy-6-methylbenzyl)-1-piperazinecarbodithioate were added 7 ml of 1-N hydrochloric acid and 17 ml of methanol. The mixture was chilled with ice, and to the mixture was dropwise added a solution of 1.76 g (7.52 mmol.) of FeCl3.6H2O in 5 ml of water. The resulting homogeneous red-colored solution was stirred for 30 min. and placed under reduced pressure at a temperature of lower than 50° C. to distill off methanol. To the residue was added 50 ml of ethyl acetate, and further added portionwise a saturated aqueous sodium hydrogen carbonate solution to adjust the solution to pH 10. A precipitated brownish red solid was removed by filtration. Thus obtained organic filtrate was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was crystallized from ethanol, and collected by filtration, to give 540 mg of the desired compound as an orange-brown crystalline powder, m.p. 115°-116° C., yield 77.6%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH:10](Br)[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)Br)=[CH:5][CH:4]=1)#[N:2].[CH3:23][O:24][Na].O>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[O:24][CH3:23])=[CH:5][CH:4]=1)#[N:2]
Reactant: CO[Na]
Reactant: N#Cc1ccc(C(=O)C(Br)C(Br)c2ccc(C#N)cc2)cc1
Solvent: CO
Solvent: O
Product: COC(=CC(=O)c1ccc(C#N)cc1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 15 g (35.9 mmol) dibromochalcone ii in 150 mL dry MeOH (distilled from Mg metal) was heated to reflux. Freshly prepared 3N MeONa (2.49 g Na in 36 mL MeOH) was added dropwise, and stirring was continued for 30 min. The clear orange solution was cooled to room temperature, and poured into 100 mL water. The aqueous suspension was extracted with CH2Cl2 and the solvent was removed under reduced pressure. The oily orange residue crystallized in part, and was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[S:10])SC.O.[NH2:12][NH2:13]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[S:10])[NH:12][NH2:13]
Reactant: NN
Reactant: COCCCNC(=S)SC
Solvent: CCO
Solvent: O
Product: COCCCNC(=S)NN
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 98.5 %

Procedure:
A solution of methyl N-(3-methoxypropyl)-dithiocarbamate (100.2 g) in ethanol (300 ml) was added dropwise at 3° C. over 30 minutes to a solution of hydrazine hydrate (28 g) in ethanol (200 ml). The mixture was stirred for 4.5 hours at 70° C. The reaction mixture was concentrated and to the residue were added water and diethyl ether. The diethyl ether extract was dried over magnesium sulfate and evaporated in vacuo to give pinkish oil of 4-(3-methoxypropyl)thiosemicarbazide (89.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33](Cl)=[O:34])(=[O:30])=[O:29].C(OCC)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][N:12]([C:33](=[O:34])[C@@H:32]3[CH2:36][CH2:37][CH2:38][N:31]3[S:28]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)(=[O:30])=[O:29])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Reactant: O=C(Cl)[C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C([C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
To a solution of (±)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (10.01 g, 0.038 mole) in pyridine (150 ml) is added (S)-N-(2-naphthalenesulfonyl)prolyl chloride (18.57 g, 0.057 mole), and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added ethyl acetate, and the mixture is washed with 5% hydrochloric acid, water, aqueous sodium hydrogen carbonate solution, water and saline in this order, and the ethyl acetate layer is separated, dried over sodium sulfate and distilled to remove the solvent. The resulting caramel is subjected to silica gel column chromatography (hexane: ethyl acetate=5:1-3:1). From the fraction eluted first there is obtained (R)-2-(4-chlorophenyl)-4-[(S)-N-(2-naphthalenesulfonyl)prolyl]-3,4-dihydro-2H-1,4-benzothiazine (10.75 g, 51%) as crystals. M.p. 147°-151° C.
Reaction SMILES: [Na].[OH:2][C:3]([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[C:4]#[N:5].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C)C=O>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:2][C:3]([C:6]([F:7])([F:9])[F:8])([C:10]([F:11])([F:12])[F:13])[C:4]#[N:5])=[CH:17][CH:16]=1
Reactant: N#CC(O)(C(F)(F)F)C(F)(F)F
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: N#CC(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionitrile sodium salt (43 g.), 4-chlorobenzyl chloride (25.6 g.) and dimethylformamide (200 ml.) is stirred at ambient temperature for 5 days, then evaporated in vacuo. Water is added to the residue, and the mixture is extracted with 1,2,2-trichloro-1,1,2-trifluoroethane. The extract is dried with sodium sulphate, and evaporated. The residue is distilled to give 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionitrile, b.p. 54°-64° C. at 1 mm. pressure (41.0 g.).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:14]=[CH:13][C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][S:4][C:5]3[CH:14]=[CH:13][C:8]([NH:9][C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=3)[CH2:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1ccc(SCCCl)cc1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(SCCN2CC=C(c3ccc(F)cc3)CC2)cc1

Procedure:
1.8 G. of 4'-[(2-chloroethyl)thio]acetanilide, 2.7 g. of 4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine, 4.5 g. of potassium carbonate and a few crystals of potassium iodide are heated under reflux conditions in 50 ml. of ethanol and 5 ml. of water for 16 hours. The solvent is evaporated under reduced pressure, the residue is taken up in chloroform and washed with water. From the organic phase there is obtained crude 4'-{[2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]-ethyl]thio}acetanilide which melts at 150°-152°C. after recrystallization from acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:9]([O:16][C:17](=[O:18])[NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)C[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.8 %

Procedure:
To a solution of L-leucinol (1.00 g, 8.53 mmol) in methylene chloride (30 ml) were added chloroformic acid benzyl ester (1.46 ml, 10.2 mmol) and triethylamine (1.43 ml, 10.2 mmol) in an ice bath, and the mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed With saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford [(1S)-1-(hydroxymethyl)-3-methylbutyl]carbamic acid benzyl ester (2.31 g, yield 100%) as a colorless oil.
Reaction SMILES: [CH:1]1[C:2]2[CH:22]=[CH:21][C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH:13]=[CH:12][C:11]=3[C:3]=2[O:4][C:5]=1[C:6](OCC)=[O:7].[BH4-].[Li+]>>[CH:1]1[C:2]2[CH:22]=[CH:21][C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH:13]=[CH:12][C:11]=3[C:3]=2[O:4][C:5]=1[CH2:6][OH:7]
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2o1
Agent: [BH4-]
Agent: [Li+]
Product: OCc1cc2ccc3c4ccccc4ccc3c2o1
Yield: 90.3 %

Procedure:
To a RB flask equipped with magentic stirring bar, reflux condenser, N2 inlet tube with bubbler was added ethyl phenanthro(1,2-b]furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 7.9 g, 27.2 mmol), lithium borohydride (Aldrich, 0.65 g, 30 mmol) and dry THG (400 mL). The mixture was stirred at reflux for 6 h and then poured into H2O (1 L). The reaction mixture was acidified with 1N HCl and the resulting white solid was filtered, washed with additional H2O (1500 mL) then dissolved in CH2Cl2 (500 mL), dried (Na2SO4), filtered, concentrated to 200 mL and diluted to 500 mL with hexane. The resulting material was filtered, washed with hexane (100 mL) and placed in a vacuum oven overnight. A total of 6.1 g (90.1%) of phenanthro[1,2-b]furan-2-methanol, mp 125°-126° was obtained (C, H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2C=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:9]2)[N:5]=[CH:4][N:3]=1.[NH4+:27].[OH-]>>[NH2:27][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:8]2[C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:9]2)[CH:7]=1
Reactant: Fc1ccc(C2=CN(c3cc(Cl)ncn3)NC(c3ccccc3)=N2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1cc(-n2nc(-c3ccccc3)nc2-c2ccc(F)cc2)ncn1
Temperature: 120 °C

Procedure:
A mixture of 1-(4-chloropyrimidin-6-yl)-3-phenyl-5-(4-fluorophenyl)-1,2,4-triazine (0.080 g, 0.23 mmol) and concentrated NH4OH was heated to 120° C. for 18 h in a sealed reaction vessel. After cooling the reaction to ambient temperature, the precipitate which had formed was collected and washed with water, air-dried and dried in vacuo at 40° C. to afford the title compound as a white solid; yield 0.030 g (39%): ES MS m/z=333 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[CH3:14][S:15](Cl)(=[O:17])=[O:16].Cl>N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3)(=[O:17])=[O:16]
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C1(CC1)O2

Procedure:
To a solution of 5-aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.519 g.) in pyridine (5 ml.) was added methanesulfonyl chloride (0.28 ml.) under ice-cooling, followed by stirring. The reaction mixture was poured into cooled dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to remove the solvent. The residue was recrystallized from ethanol. By the above procedure there was obtained 5-methylsulfonylaminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as colorless needles melting at 152°-154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([S:6]/[C:7](=[C:11](\[OH:15])/[C:12]([OH:14])=[O:13])/[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(Cl)=[S:25]>C1COCC1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([S:6]/[C:7](=[C:11](\[OH:15])/[C:12]([OH:14])=[O:13])/[C:8]([OH:10])=[O:9])=[CH:16][CH:17]=1)=[C:24]=[S:25]
Reactant: Nc1ccc(S/C(C(=O)O)=C(\O)C(=O)O)cc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)/C(O)=C(/Sc1ccc(N=C=S)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 2-[4'-(amino)thiophenoxy]-3-hydroxymaleic acid (0.370 g, 1.438 mmol) and freshly powdered, freshly dried K2CO3 (1.217 g, 8.806 mmol in THF (30 mL) under nitrogen was added thiophosgene (0.33 mL, 0.498 g, 4.33 mmol). The reaction mixture was stirred vigorously at room temperature for 1 hour, then at reflux for 30 minutes. Upon cooling to room temperature, the reaction mixture was filtered and the solvent evaporated off to afford crude 2-[4'-(isothiocyanato)-thiophenoxy]-3-hydroxymaleic acid as an orange oil; (This material was used directly in the next step but could be crystallized from CHCl3) MP 156°-158° C. with decomposition; 1H NMR (acetone-d6, d) 10.2 (2H, br), 7.58 (2H, d, J=8.8 Hz), 7.32 (2H, d, J=8.8 Hz), 4.99 (1H, br s), 4.79 (1H, d, J=4.8 Hz), 4.26 (1H, d, J=4.8 Hz); 13C NMR (acetone-d6, d) 172.7, 171.0, 135.7, 133.7, 130.9, 127.1, 127.0, 71.7, 55.7; IR (Nujol mull, cm-1) 3390 (br, m), 2040 (s), 1730 (s), 1695 (s); mass spectrum, m/e 299, 263, 191, 166, 108, 57 (base).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[CH2:13][NH:14][C:15](=[O:17])[CH3:16]>ClC(Cl)C>[Cl:1][CH2:2][C:3]([C:20]1[CH:19]=[CH:18][C:12]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])=[C:11]([CH3:10])[CH:21]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)NCc1ccccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)NCc1ccc(C(=O)CCl)cc1C
Temperature: 0 °C
Yield: 29.7 %

Procedure:
Chloroacetyl chloride (17 g) was added dropwise to a mixture of aluminum chloride (13.3 g) in dichloroethane (60 ml) at ambient temperature under stirring and the mixture was stirred for one hour. To the resulting mixture was added N-(2-methylbenzyl)acetamide (13.3 g) at ambient temperature and the mixture was stirred at 25° to 50° C. for 1.5 hours. The reaction mixture was poured into ice water and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was washed with ethyl acetate and diisopropyl ether to give N-(4-chloroacetyl-2-methylbenzyl)acetamide (5.8 g).
Reaction SMILES: [OH2:1].Cl.[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH3:9][C:3]1[CH:8]=[CH:7][C:6]([C:4]2[C:3]([C:9]([OH:1])=[O:1])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1
Reactant: O
Agent: Cl
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 170 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
The resulting reaction solution was stirred at 170° C. for 8 hours, and then cooled to 90° C. To this reaction solution was added dropwise 177.5 g of water. After the completion of dropwise addition, the mixture was stirred for 30 minutes. To this mixture was added 66.6 g of toluene, and 52.64 g (505.3 mmol) of 35% hydrochloric acid was further added dropwise. The temperature inside the flask was raised to 75° C. to dissolve the resulting product in toluene and form into two layers. After the solution was allowed to stand to separate into layers, the lower aqueous layer was removed therefrom. The toluene layer was dehydrated over anhydrous magnesium sulfate, and then gradually cooled to allow sedimentation of white crystals of 4′-methylbiphenyl-2-carboxylic acid. The temperature was lowered to 0° C., and its temperature was maintained for one hour, and then the crystals were filtered. After the crystals were washed with 20 g of toluene at 0° C., the crystals were air-dried to give 44.1 g of white crystals of 4′-methylbiphenyl-2-carboxylic acid (yield: 90.4% based on 2-cyano-4′-methylbiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 150.1° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccc(F)c2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13i, and 3-fluorobenzenesulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. MS 569 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[C:5]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(#N)C>[Br:19][C:3]1[C:2]([OH:1])=[C:7]([C:6]([CH3:13])=[C:5]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(O)ccc(OS(C)(=O)=O)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1c(C)c(OS(C)(=O)=O)cc(Br)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
To a solution of ethyl 6-hydroxy-2-methyl-3-((methylsulfonyl)oxy)benzoate (116c, 1.3 g, 4.8 mmol) in acetonitrile (63 mL) was added N-bromosuccinimide (1.1 g, 6.2 mmol). The reaction was stirred at room temperature for 20 hours. The reaction mixture was concentrated under vacuum then diluted with water (30 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (30% EtOAc/Heptane) to give ethyl 3-bromo-2-hydroxy-6-methyl-5-((methylsulfonyl)oxy)benzoate (116d, 1.3 g, 79% yield) as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=3[CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]3=[O:51])=[CH:41][C:40]=2[F:52])=CC=1)([O-])=O>>[F:52][C:40]1[CH:41]=[C:42]([N:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]2=[O:51])[CH:43]=[CH:44][C:39]=1[NH:38][C:37]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=3[CH:21]=2)=[O:16])[CH2:9]1)=[O:36]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1cc2cc(Cl)ccc2o1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc2cc(Cl)ccc2o1

Procedure:
67.3 Using general method H, 5-chloro-benzofuran-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-chloro-benzofuran-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale yellow solid. MS 507.0 ([M−H]−)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[K+].[CH3:14][O:15][C:16](=[O:21])[CH2:17]C([O-])=O>>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10](=[O:12])[CH2:17][C:16]([O:15][CH3:14])=[O:21])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)CC(=O)[O-]
Agent: [K+]
Product: COC(=O)CC(=O)Cc1cc(Cl)cc(Cl)c1
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield from 2-(3,5-dichlorophenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A.