Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43].CCN(C(C)C)C(C)C.[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:42]([NH:44][C:45](=[O:46])[NH:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:3]=1)[CH3:43]
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CCN=C=O
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (25 mg, 0.046 mmol) in DCM (1 ml) was added ethyl isocyanate (5.51 μl, 0.070 mmol) and DIEA (0.024 ml, 0.139 mmol). The vial was capped and the contents stirred at room temperature for 16 h. The course of reaction was followed by LCMS analysis. Only minor product formation was observed. Excess isocyanate (1.5 eq) was added and the reaction mixture heated to 40° C. for a further 16 h. Unreacted isocyanate was quenched by adding MP-Trisamine (229 mg, 0.464 mmol) and tumbling the vial for 3 h. The resin was filtered and the volatiles removed in vacuo to afford crude (R)-1-(3-(3-ethylureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea which was taken forward without purification. MS ESI calc'd. For C37H36N7O2 [M+H]+ 610. found 610.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][CH3:73]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:72][CH3:73])[CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Br)ccc32)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 92 (0.4 g, 0.66 mmol), was reacted with diisopropylethylamine (0.77 g, 5.9 mmol), diphenylphosphinic chloride (0.62 g, 2.6 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.29 g, 2.0 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a off white solid (Yield 0.15 g, 36%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[O:14]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Sc1ccccc1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCC(=O)c1ccc(Sc2ccccc2)cc1
Temperature: 110 °C
Yield: 75.5 %

Procedure:
4-(4-Fluoro-phenyl)-4-oxo-butyric acid (10.0 g, 51 mmol), thiophenol (5.2 g, 51 mmol) and powdered potassium carbonate (13.8 g, 100 mmol) were added to 25 mL of dimethyl sulfoxide (DMSO). The reaction mixture was heated to 110° C. for 2 hours, then cooled and diluted by addition of 250 mL water. The aqueous mixture was extracted three times with 100 mL of EtOAc, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to yield 11 g (38.5 mmol, 75.5%) of 4-oxo-4-(4-phenylsulfanyl-phenyl)-butyric acid as a crude solid. MS: 287 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[C:33]([NH2:36])(=S)[CH3:34].O>CN(C=O)C>[NH2:36]/[C:33](/[CH3:34])=[CH:2]\[C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C(O)c1ccc(Cn2c(C(=O)CBr)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Reactant: CC(N)=S
Solvent: O
Solvent: CN(C)C=O
Product: C/C(N)=C/C(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 51.2 %

Procedure:
To a solution (6 ml) of 4-[[3-(2-bromoacetyl)-6-chloro-1-oxo-4-phenyl-1H-isoquinolin-2-yl]methyl]benzoic acid (570 mg) in DMF was added thioacetamide (170 mg), and the mixture was stirred at 70° C. for 24 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (270 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[O:12]1[CH:14]([CH3:15])[CH2:13]1>>[OH:12][CH:14]([CH3:15])[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: CC1CO1
Product: CCc1cccc(CC)c1NCC(C)O
Yield: 44.7 %

Procedure:
2,6-Diethylaniline is reacted with 1,2-epoxypropane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxypropyl)-2,6-diethylaniline with a yield of 44.7%; b.p.: 137°-145° C./1 mm Hg.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].[Br:13]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:10]1[CH:9]=[CH:8][C:7]2[NH:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCCc2ccccc2N1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(Br)ccc2N1

Procedure:
To a solution of the title compound from Example 2 Step B (17.0 g, 106 mmol) in N,N-dimethylformamide (500 mL) was added N-bromosuccinimide (25.2 g, 141 mmol) at room temperature, and then the mixture was refluxed for 16 hours. The reaction mixture was diluted with ethyl acetate (1 L), and the separated organic layer was washed with 0.1 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether:ethyl acetate=12:1 to 3:1) provided a crude product that was recrystallized from ethyl acetate and petroleum ether (v:v=1:10) to give the title compound: LCMS m/z=241 [M+2+H]+. 1H NMR (400 MHz, d6-DMSO): δ 9.56 (s, 1H), 7.46 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 2.65 (m, 2H), 2.12-2.07 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([NH:10][C:11](=[O:13])[CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:11]([NH:10][CH:2]([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][CH:9]=1)(=[O:13])[CH3:12]
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)NC(C)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)NC(C)Cc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a one l., three necked, creased flask provided with a stirrer, thermometer, condenser topped with a drying tube and a short length of Gooch tubing connected to a small Erlenmeyer flask was placed 18.7 g (0.106 moles) of N-(alpha-methylphenethyl) acetamide, 15.9 g (0.159 moles) of succinic anhydride and 500 ml of dry methylene chloride. The flask and contents were cooled to 0°-5°, and from the Erlenmeyer flask through the Gooch tubing, 55.5 g (0.424 moles) of anhydrous aluminum chloride was added in small portions over a period of approximately 0.5 hour. A sharp exotherm occurred after each of the first additions, but the temperature was not allowed to exceed 8°. During the addition, the succinic anhydride slowly dissolved and gradually a grayish green gum was deposited. After five hours at 0°-5°, the cooling bath was removed, and the stirred mixture allowed to warm to room temperature (19°-22°), then stirred for another twenty-four hours. At the end of this time, the reaction mixture consisted of a reddish orange gum and a pale-colored solvent. The mixture was cooled in an ice bath, and with vigorous stirring 200 ml of 3 N hydrochloric acid added at 20°. The mixture was stirred until the color of the viscous red gum became grayish white. The stirrer was then stopped, the layers allowed to separate, and the lower methylene chloride layer removed by suction from the reaction vessel. Another 300 ml of methylene chloride was added to the flask, the contents stirred for five minutes, then allowed to settle and the lower layer drawn off as before.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:15][CH2:14]2)[C@H:11]([C:16]([O:18]CC)=[O:17])[O:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O>CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:15][CH2:14]2)[C@H:11]([C:16]([OH:18])=[O:17])[O:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1OC(c2ccc(OC)cc2)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C2O[C@@H](C(=O)O)[C@H](C3CC3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 881 mg of ethyl (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate (diastereomeric mixture) in 16 ml of methanol is added dropwise a solution of 64.7 mg of lithium hydroxide in 8 m 1 of water under cooling, and the mixture is stirred at room temperature for 1 hour. After the reaction mixture is evaporated under reduced pressure to remove methanol, the residue is dissolved in chloroform. The pH of the solution is adjusted to pH 2 with 10% hydrochloric acid. After extracted with chloroform, the extract is washed with brine twice, dried and evaporated to remove the solvent to give 792 mg of (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([Cl:7])=[O:6].[Cl:12]Cl>[Fe](Cl)(Cl)Cl>[Cl:12][C:3]1[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[CH:8][C:4]=1[C:5]([Cl:7])=[O:6]
Reactant: ClCl
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: Cl[Fe](Cl)Cl
Product: Cc1cc(C)c(Cl)c(C(=O)Cl)c1
Yield: 64.8 %

Procedure:
A stirred apparatus with gas feed and discharge to an eliminator was initially charged with 100 g (0.593 mol) of 3,5-dimethylbenzoyl chloride together with 0.5 g of iron (III) chloride, and 42 g of chlorine were introduced at 22-28° C. over the course of 3 hours. Fractional distillation gave 78 g of 2-chloro-3,5-dimethylbenzoyl chloride. Boiling range: 113-114° C. at 5 mbar.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]=[C:4](SC)[CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]=[C:4]([NH:30][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCc1ccccc1
Reactant: CSC1=Nc2ccccc2C(=O)N(C)C1c1ccccc1
Product: CN1C(=O)c2ccccc2N=C(NCCc2ccccc2)C1c1ccccc1
Temperature: 240 °C
Reaction time: 1 h

Procedure:
A mixture of 7.41 g (0.025 m) of 3,4-dihydro-4-methyl-2-methylthio-3-phenyl-5H-1,4-benzodiazepine-5-one and 12.11 g (0.100 m) of phenethylamine is heated in an oil bath for 6 hours. The temperature of the oil bath is slowly raised to 240° C and held there for 1 hour. After cooling to room temperature, the residual oil is crystallized from ether to give the crude product, 3,4-dihydro-4-methyl-2-phenethylamino-3-phenyl-5H-1,4-benzodiazepine-5-one. Recrystallization from ethyl acetate and ethyl acetate-ether gives a pure product, 3,4-dihydro-4-methyl-2-phenethylamino-3-phenyl-5H-1,4-benzodiazepine-5-one, a white solid, m.p. 173°-174.5° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:7](O)=[O:8]>>[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:7]([Cl:3])=[O:8]
Reactant: CCCCCCCCC(C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCC(C)C(=O)Cl
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
To thionyl chloride (93 g, 782 mmol), cooled to 15° C. in a water bath was added during 1 hour 2-methyl decanoic acid (64 g, 344 mmol). The cold water bath was removed and the mixture was heated at 50° C. with stirring for 45 minutes. The excess thionyl chloride was removed by distillation and the crude acid chloride was then fractionally distilled (b.p. 143°-45° C./5.8 mm) to give 69 g of product (99% yield) that showed an assay of >98% by GC.
Reaction SMILES: [CH:1]([N:5]=[N:6][C:7]([N:13]=[C:14]=[O:15])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH2:3][CH3:4])[CH3:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCCCC>[CH:1]([N:5]=[N:6][C:7]([NH:13][C:14]([NH:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])([CH3:8])[CH2:9][CH:10]([CH3:11])[CH3:12])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N=NC(C)(CC(C)C)N=C=O
Reactant: NC1CCCCC1
Solvent: CCCCC
Product: CCC(C)N=NC(C)(CC(C)C)NC(=O)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
To 5.3 grams (.025 moles) of stirred 2-sec.-butylazo-2-isocyanato- 4-methylpentane (from Example XVII) in a 50 ml erlenmeyer flask was added 2.6 grams (.026 moles) of cyclohexylamine. A solid quickly formed so 25 ml of pentane was added and the slurry stirred for approximately 1/2 hour, the solid filtered, reslurried in 25 ml of fresh pentane and refiltered. The solid was air dried and weighed. The white powder weighed 4.4 grams (57% crude yield) and had a melting range of 118 to 123° C. The infrared spectrum of the product was in agreement with the structure of N-[1-(sec.-butylazo)-1,3-dimethylbutyl]-N'-cyclohexylurea(sharp NH at 3250 cm-1 and strong carbonyl band at 1625 cm-1).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.Cl[C:24]1[NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[N:25]=1>C(O)CCC.C(N(CC)CC)C>[NH:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[N:20]1[CH2:21][CH2:22][N:17]([C:5]2[N:4]=[C:3]([NH2:2])[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)[CH2:18][CH2:19]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(c4nc5ccccc5[nH]4)CC3)nc(N)c2cc1OC
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To 5.14 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride in 100 ml butanol, 11 ml of triethylamine was added. The mixture was stirred for 15 min and 2.65 g of 2-chloro-1H-benzimidazole was added. The mixture was refluxed for 18 hr and evaporated. Water was added to the residue and the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate and evaporated. The residue was crystallized from methanol to give 3.5 g of the title compound, which was recrystallized from methanol: mp>250° C.; ir (nujol mull) 3360 and 3180 cm-1 ; uv max (MeOH) 341 (ε=6,300), 284 (ε=28,500) and 251 nm (ε=66,800); nmr (DMSO-d6) ε 3.5 (m, 4H), 3.8 (m, 4H), 3.8 (s, 3H), 3.84 (s, 3H), 7.1 (m, 8H) and 10.7 (s, 1H); and Anal. Calcd for C21H23N7O2. 1/2 H2O: C, 60.86% H, 5.79% N, 23.67% and Found: C, 60.87% H, 5.98% N, 23.65%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][C:9]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][C:9]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC1(c2ccccc2)CC2(NC(=O)NC2=O)c2cc(Br)ccc2O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(c2ccccc2)CC2(NC(=S)NC2=O)c2cc(Br)ccc2O1
Yield: 61.8 %

Procedure:
A suspension of 6-bromo-2-methyl-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (1.16 g, 3 mmol) and Lawesson's Reagent (1.21 g, 3 mmol) in dry 1,4-dioxane (24 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column to give 6-bromo-2-methyl-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (748 mg, 61%). 1H-NMR (CDCl3): 1.75 (s, 3H), 3.78 (m, 2H), 5.79 (s, 1H), 6.94 (m, 1H), 7.14 (m, 1H), 7.22 (m, 1H), 7.26-7.53 (m, 5H), 8.39 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)C.O.[OH-].[Na+]>CCO>[CH:25]1([O:24][C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([CH2:5][C:4]([OH:30])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])[CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CC1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(CC(=O)O)Cc3ccccc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
A solution of the 2-(2-cyclobutyloxy-3-methylbenzoylamino)indan-2-acetic acid ethyl ester (288) (400 mg-1 mmol) in EtOH (15 mL)/water (1 mL) is treated with NaOH pellets (800 mg-20 mmol) and stirred at RT for 24 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with HCl to pH 2-3. The product is extracted into EtOAc (3×20 mL) and the combined extracts washed with water (2×10 mL) and brine (2×15 mL). The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is triturated with heptane and the pure product isolated by filtration to give white solid (350 mg, 92%).
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]([C:13]([NH:15][CH2:16][C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][C@@H:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C@H:21]2[C:33]([OH:35])=[O:34])=[O:18])=[O:14])=[CH:11][C:10]=1[C:38]([CH3:41])([CH3:40])[CH3:39])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:29]([O:28][C:26]([C@H:23]1[CH2:22][C@@H:21]([C:33]([OH:35])=[O:34])[C@@H:20]([NH:19][C:17](=[O:18])[CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:36]=[CH:37][C:9]([OH:8])=[C:10]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:11]=2)[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2ccc(OCc3ccccc3)c(C(C)(C)C)c2)[C@H](C(=O)O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2ccc(O)c(C(C)(C)C)c2)[C@H](C(=O)O)C1
Yield: 107.4 %

Procedure:
A suspension of (1R,2S,5R)-2-(2-(4-(benzyloxy)-3-tert-butylbenzamido)acetamido)-5-(tert-butoxycarbonyl)cyclohexanecarboxylic acid (100 mg, 0.17 mmol) and 10% Pd/C (100 mg) in MeOH (10 mL) was exposed to an atmosphere of hydrogen for 14 h. The reaction mixture was filtered through diatomaceous earth, rinsed with MeOH (400 mL) and concentrated in vacuo to provide (1R,2S,5R)-5-(tert-butoxycarbonyl)-2-(2-(3-tert-butyl-4-hydroxybenzamido)acetamido)cyclohexanecarboxylic acid (87 mg, quant.) as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.79-7.78 (m, 1H), 7.61-7.58 (m, 1H), 6.80-6.75 (m, 1H), 4.59 (s, 1H), 3.99 (s, 2H), 3.45-2.89 (m, 4H), 2.54 (s, 1H), 2.18-1.25 (m, 6H), 1.42 (s, 9H), 1.41 (s, 9H); MS found: (M+H)+=492.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:10])[CH:7](O)[C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O>C(Cl)Cl.N1C=CC=CC=1>[Cl:20][CH:7]1[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1(C)Oc2ccc(Cl)cc2C1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(C)Oc2ccc(Cl)cc2C1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 27.9 grams (0.109 mole) of 5-chloro-2-ethoxycarbonyl-2,3-dihydro-3-hydroxy-2-methylbenzofuran in 200 mL of methylene chloride was stirred, and four drops of pyridine was added. The reaction mixture was cooled in an ice-water bath, and 19.4 grams (0.163 mole) of thionyl chloride was added dropwise. The reaction mixture was then stirred for about 30 minutes at the ice-water bath temperature, and allowed to warm to ambient temperature, where it stirred for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue, which was diluted with water and ethyl acetate, and washed with a solution saturated with sodium bicarbonate. The aqueous layer was separated and washed with two portions of ethyl acetate. The organic layer and the ethyl acetate washes were combined and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with 1:9 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 27.3 grams of 3,5-dichloro-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][C@H:6]([NH:20][C:21](C1C=C(C)N=C(N(CCC)CCC)N=1)=[O:22])[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1.[CH2:41]([C:45]1[N:49]2[CH:50]=[C:51](C(O)=O)[CH:52]=[CH:53][C:48]2=[N:47][CH:46]=1)[CH2:42][CH2:43][CH3:44]>>[CH2:41]([C:45]1[N:49]2[CH:50]=[C:51]([C:21]([NH:20][C@@H:6]([CH2:5][C:4]3[CH:3]=[C:2]([F:1])[CH:39]=[C:38]([F:40])[CH:37]=3)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=3)=[O:22])[CH:52]=[CH:53][C:48]2=[N:47][CH:46]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCN(CCC)c1nc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)n1
Reactant: CCCCc1cnc2ccc(C(=O)O)cn12
Product: CCCCc1cnc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cn12

Procedure:
In the same manner as for N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(dipropylamino)-6-methylpyrimidine-4-carboxamide {Example S-SP-235}, Step 3, 3-butylimidazo[1,2-a]pyridine-6-carboxylic acid (0.16 g) was converted to 0.30 g of the title compound.