Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CCO>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]([C:14]([O:16][CH3:17])=[O:15])=[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N
Solvent: CCO
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C

Procedure:
The title compound was prepared following the procedure described in WO2003/033476. Condensation of 2.00 g of methyl 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylate with dimethylformamide dimethyl acetal for 3 hr in refluxing EtOH yielded 2.52 g (100%) after removal of the volatiles under vacuum. 1H NMR (CDCl3) δ 3.06 (s, 3H), 3.08 (s, 3H), 3.81 (s, 3H), 6.98 (s, 1H), 7.35 (d, J=8.79 Hz, 2H), 7.53 (d, J=8.24 Hz, 2H), 7.69 (s, 1H); 13C NMR (CDCl3) δ 34.31, 40.26, 51.44, 112.43, 122.28, 126.95, 129.09, 132.18, 134.45, 145.79, 156.09, 159.16, 163.22. HPLC (Method #1): 2.45 min retention time. MS (ES): m/z 323 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[C:14](Cl)(=[O:16])[CH3:15]>>[C:14]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CC(=O)Cl
Product: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1

Procedure:
Methyl 3-acetylindole-6-carboxylate (470 mg) was prepared from methyl indole-6-carboxylate (655 mg) and acetyl chloride (0.27 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O)=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[O:6][CH2:7][C:8]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:10])=[O:2]
Reactant: Nc1ccncc1
Reactant: Cc1cc(C=O)cc(OCC(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(OCC(=O)Nc2ccncc2)c1
Yield: 61.1 %

Procedure:
2-(3-Formyl-5-methyl-phenoxy)-acetic acid (0.47 g) and 4-aminopyridine (0.46 g) were dissolved in dry DMF (10 ml). The resulting solution, stirring under a nitrogen atmosphere, was treated with TBTU (0.82 g). The resulting mixture was stirred for 68 h and then concentrated at reduced pressure to give a yellow viscous gum. This crude material was purified by preparative hplc. The purified product was partitioned between ethyl acetate and an aqueous solution saturated with sodium bicarbonate, sodium chloride and ammonium sulphate. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure giving the title compound as an off-white solid (0.40 g).
Reaction SMILES: [OH:1][C:2]1[C:3](C)=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1.[C:28](O)(C(F)(F)F)=[O:29].O.C(O)(C(F)(F)F)=O.CC#N>>[OH:1][C:2]1[C:3]([O:29][CH3:28])=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Solvent: O
Solvent: CC#N
Product: COc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.13 h
Yield: 76 %

Procedure:
The title compound (26 mg, 76%) was prepared from Example 398 (38 mg, 0.092 mmol) by a route analogous to that used for the preparation of compound 397A. It has a retention time of 6.08 min. (Column: HTS, 5 u, 4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H2O; B=0.1% TFA/CH3CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M+H)+=373.2
Reaction SMILES: S(=O)(=O)(O)O.[C:6](O)(=O)[C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:13][NH:14][C:15](=[S:18])[NH:16][NH2:17].N>C1(C)C=CC=CC=1.O>[C:7]([C:6]1[S:18][C:15]([NH:14][CH3:13])=[N:16][N:17]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)O
Reactant: CNC(=S)NN
Agent: N
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1nnc(C(C)(C)C)s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Into a four-necked, 1-liter flask equipped with a stirrer, thermometer and a drying tube was charged a solution of 115% polyphosphoric acid (63.98 g) and 96.2% sulfuric acid (21.33 g). A solution of pivalic acid (21.48 g, 0.2107 mole) and toluene (1.82 g) was added followed by 4-methyl-3-thiosemicarbazide (22.1 g, 0.2102 mole). The mixture was stirred with the initial reaction exotherm being controlled with cooling if necessary such that the reaction temperature did not rise above 70° C. The reaction mixture was then maintained with stirring and heating for about 1 hour at 70° C. The reaction flask was then fitted with two dropping funnels. The first funnel contained 256 g of a solution consisting of 192 g of 115% polyphosphoric acid and 64 g of 96.2% sulfuric acid. The second funnel contained a mechanically stirred slurry of 4-methyl-3-thiosemicarbazide (66.3 g, 0.631 mole) in pivalic acid (64.45 g, 0.632 mole) and toluene (5.45 g). The contents of the two dropping funnels were added simultaneously to the stirred reaction mixture (reaction "heel") over a period of 45 minutes, the reaction temperature being maintained at 70° C. The temperature was then increased to 80° C. and held for about 1 hour. The contents of the flask were then poured slowly into a stirred mixture of 28% aqueous ammonia (445 ml), water (210 ml) and toluene (40 ml) contained in a 2-liter beaker. The temperature was allowed to rise to 75°-80° C. and the pH of the aqueous phase was adjusted to 6.1 by the addition of 150 ml of 28% ammonia. The aqueous and organic phases were separated while hot (75° C.). The product, 5-t-butyl-2-methylamino-1,3,4-thiadiazole was isolated as a yellow to orange solid in 98% yield, melting point 78°-80° C., by evaporation of the organic phase to dryness under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C([O-])(=O)C.[Na+].[OH:17][C:18]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:19]=1[CH2:20]Cl>>[OH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH:1][CH2:20][C:19]1[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:18]=1[OH:17]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=[N+]([O-])c1ccc(O)c(CCl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(O)c(CNc2cc([N+](=O)[O-])ccc2O)c1
Reaction time: 2 h

Procedure:
15.4 g. of 2-amino-4-nitrophenol and 8.2 g. of sodium acetate were added to 200 ml. of an alcohol and the mixture was heated under reflux. To the mixture was added dropwise 19.6 g. of 2-hydroxy-5-nitrobenzyl chloride dissolved in 70 ml. of an alcohol over a period of time of 30 minutes. After the reaction was effected for about 2 hours, the alcohol was distilled off. The reaction mixture was extracted with ethyl acetate and the extract was washed with water and concentrated by distilling off the ethyl acetate to have crystals precipitated. The crystals were recrystallized from 250 ml. of acetonitrile to obtain the end product. The melting point of the end product was 170°-220° C. (decomp.) and the yield was 24 g.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 95.2 %

Procedure:
A mixture of 4-fluorobenzaldehyde (2.0 g, 0.0161 mol), 4-tert-butylphenol (2.42 g, 0.161 mol), and K2CO3 (9.0 g, 0.065 mol) in DMF (50 mL) was heated at 80° C. After 6 h, the reaction mixture was filtered into ice/water and the product was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), concentrated and chromatographed with 1:1 hexane/ethyl acetate to give 3.9 g (95%) of 4-(4-tert-butylphenoxy)benzaldehyde.
Reaction SMILES: [C:1]([O:4][C:5]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([CH3:20])[CH:6]=1)(=[O:3])[CH3:2].CC1CCCCCCCCCCCCC(=O)C1>>[C:1]([O:4][C:5]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]([CH3:20])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1=CC(C)CCCCCCCCCCCC1
Agent: CC1CCCCCCCCCCCCC(=O)C1
Product: CC(=O)OC1=C[C@@H](C)CCCCCCCCCCCC1

Procedure:
Mixed in 20 mL of a phosphate buffer (pH 7) were 2.0 g of dl-3-methylcyclopentadecene-1-yl acetate as obtained in Example 1 (a) and 1.0 g (50 wt. % relative to the substrate) of the immobilized enzyme (Novozyme 435) originating from Candida antarctica, followed by vigorous shaking at 55° C. for 2 days. After the reaction, 20 mL of hexane was added to the reaction solution for extraction, and analysis of the hexane layer showed that the conversion of the substrate was 69.8% and that 3-methylcyclopentadecanone was produced, while 3-methylcyclopentadecene-1-yl acetate remained. The hexane solution was purified by silica-gel column chromatography, and 3-methylcyclopentadecanone, as produced by hydrolyzing a portion of the remained 3-methylcyclopentadecene-1-yl acetate by the conventional method, was subjected to determination of the optical purity by HPLC and identified as the (S) isomer with 90.8% ee of optical purity. Also, 3-methylcyclopentadecanone, a enzymatic hydrolysate of the substrate, was subjected to determination of the optical purity and identified as the (R) isomer with 42.6% ee of optical purity.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[O:10])[CH2:8]Br)([O-:3])=[O:2].C([O-])(=[O:16])C.[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[O:10])[CH2:8][OH:16])([O-:3])=[O:2]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CO)c1cccc([N+](=O)[O-])c1

Procedure:
Reaction of m-nitrophenacyl bromide with sodium acetate in ethanol gave m-nitrophenacyl alcohol. This was treated with dicyandiimide and HCl in aqueous methanol to give 2-guanidino4-(3-nitrophenyl)oxazole hydrochloride, m.p. 250°-251° C. The nitro residue was reduced with iron powder in acetic acid containing 10% v/v water to give 2-guanidino-4-(3-aminophenyl)oxazole.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[C:18]([O:22][C:23](=[O:30])[NH:24][C@H:25]1[CH2:28][C@H:27]([NH2:29])[CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.CC(C)([O-])C.[Na+]>ClCCl>[C:18]([O:22][C:23](=[O:30])[NH:24][C@H:25]1[CH2:28][C@H:27]([N:29]2[C:2]3=[N:7][CH:6]=[CH:5][N:4]=[C:3]3[C:8]([CH3:13])([CH3:12])[C:9]2=[O:11])[CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3nccnc32)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-(3-Chloropyrazin-2-yl)-2-methylpropanoic acid (intermediate 29, 0.302 g, 1.505 mmol) was dissolved in dichloromethane (20 mL) and treated with thionyl chloride (5.0 ml, 68.5 mmol). The solution was heated at reflux for 30 minutes then evaporated to dryness under reduced pressure. Carbon tetrachloride (20 ml) was added to the crude residue and it was evaporated to dryness once more. It was dried under high vacuum for 20 minutes. The crude acid chloride was dissolved in dichloromethane (6 mL) and added slowly to an ice cooled solution of tert-butyl(trans-3-aminocyclobutyl)carbamate (0.280 g, 1.505 mmol) and diisopropylethylamine (2.5 ml, 14.37 mmol) in dichloromethane (10 mL). The solution was stirred for 15 minutes after which the mixture was evaporated to dryness under reduced pressure and the crude dissolved in dry tetrahydrofuran (10 mL). Sodium t-butoxide (1.45 g, 15.09 mmol) was added and the reaction stirred at room temperature. After 30 minutes the reaction was partitioned between water (300 mL) and ethyl acetate (300 mL). The organic was washed with 20% saturated ammonium chloride (200 mL) then dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired tert-butyl(trans-3-(7,7-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)cyclobutyl)carbamate (0.462 g, 1.390 mmol, 92% yield). It was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (5 mL). The solution was stirred for 15 minutes. The dark solution was evaporated to dryness under reduced pressure and further dried under high vac. The crude amine was combined with purified using silica chromatography (1-20% (2N ammonia in methanol) in dichloromethane gradient) to give 5-(trans-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.294 g, 1.27 mmol, 91% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:14][C@H:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:15]([NH:14][C:9](=[O:11])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:12])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 4-tert-butoxy-4-oxobutanoic acid (2.38 g, 13.64 mmol) in DMF (30 mL) and DCM (30 mL) is added (R)-ethyl 3-amino-4-(4-bromophenyl)butanoate hydrochloride (4 g, 12.4 mmol), HATU (5.19 g, 13.64 mmol), and TEA (6.91 mL, 49.6 mmol). After stirring at room temperature for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-tert-butyl 4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate (4.0 g). HPLC retention time=1.70 minutes (condition A); MS (m+1)=444.1.
Reaction SMILES: [CH:1](=[C:3]1[CH2:8][C:7]2[CH2:9][CH:4]1[CH2:5][CH:6]=2)[CH3:2].[CH2:10]=[CH:11][CH3:12].C=C.B(C1C(F)=C(F)C(F)=C(F)C=1F)(C1C(F)=C(F)C(F)=C(F)C=1F)C1C(F)=C(F)C(F)=C(F)C=1F>C1(C)C=CC=CC=1>[CH2:1]=[CH2:2].[CH2:10]=[CH:11][CH3:12].[CH:1](=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)[CH3:2]
Reactant: CC=C1CC2=CCC1C2
Agent: C=C
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: C=CC
Solvent: Cc1ccccc1
Product: CC=C1CC2C=CC1C2
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A 2 L batch reactor is charged with 500 mL of mixed alkanes, 75 mL of 5-ethylidene-1-norbornene, and 500 mL of liquefied propylene. The reactor is heated to 60° C., and is saturated with ethylene at 500 psig (3.4 MPa). In an inert atmosphere drybox, 10 μmol of a 0.005M solution in toluene of rac-[1,2-ethanediylbis(1-(2-methyl-4-phenyl)indenyl)]zirconium (trans,trans-1,4-diphenyl-1,3-butadiene) and 10 μmol of a 0.005 m solution of B(C6F5)3 in toluene are combined and the mixture is transferred to the reactor to initiate polymerization. After 15 minutes, the reactor is vented and the solution is drained from the reactor. The polymer solution is combined with 100 mg of antioxidant and the volatiles are removed under reduced pressure in order to isolate the rubbery terpolymer of ethylene/propylene/ethylidene norbornene.
Reaction SMILES: [CH3:1]OC1C=C(C=CC=1)C=O.COC(OC)CN.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[CH:23]=[N:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].C[Mg]I>CCOCC.O.C1(C)C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[CH:23]([NH:24][CH2:25][CH:26]([O:27][CH3:28])[O:29][CH3:30])[CH3:1]
Reactant: COc1cccc(C=NCC(OC)OC)c1
Reactant: COc1cccc(C=O)c1
Agent: COC(CN)OC
Agent: C[Mg]I
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cccc(C(C)NCC(OC)OC)c1
Reaction time: 1 h

Procedure:
A solution of 13.6 g. (0.1 mole) of 3-methoxybenzaldehyde and 10.5 g. (0.1 mole) of aminoacetaldehyde dimethyl acetal in 250 ml. of toluene is refluxed for one hour and water produced in the reaction is collected in a Dean-Stark trap. The resulting solution of 3-methoxy-N-(2,2-dimethoxyethyl)benzylidenamine is added to a solution of (0.2 mole) of methylmagnesium iodide in 250 ml. of ether over 1.5 hours. The mixture is stirred for one hour, cooled and quenched by careful addition of 250 ml. of water. The aqueous phase was filtered through Celite, extracted with 150 ml. of ether and the combined organic phases washed, dried and evaporated to yield 3-methoxy-α-methyl-N-(2,2-dimethoxyethyl)benzylamine.
Reaction SMILES: C[Mg+].[Br-].[F:4][C:5]([F:15])([F:14])[C:6]1[CH:13]=[CH:12][C:9](C#N)=[CH:8][N:7]=1.CC[O:18][CH2:19][CH3:20]>>[F:4][C:5]([F:15])([F:14])[C:6]1[N:7]=[CH:8][C:9]([C:19](=[O:18])[CH3:20])=[CH:12][CH:13]=1
Reactant: CCOCC
Reactant: N#Cc1ccc(C(F)(F)F)nc1
Agent: C[Mg+]
Agent: [Br-]
Product: CC(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 2 h

Procedure:
A 3 M solution of MeMgBr in Et2O (7.2 mmol) was added to a stirred solution of 6-(trifluoromethyl)nicotinonitrile (0.82 g, 4.8 mmol) in ether (16 mL) dropwise over a 30 minute period. The reaction was stirred for 2 hours then the mixture was quenched with aqueous 1N HCl and extracted with Et2O. The organics were combined and washed with brine and dried over anhydrous MgSO4. The solvent was removed in vacuo yielding 530 mg of a brown solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:14])[C:12](=[O:15])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[CH3:32].C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:11][CH2:10]3)[C:12](=[O:15])[N:13]([CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[CH3:32])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Yield: 41 %

Procedure:
A mixture of 0.0515 g (0.000168 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53), 0.0283 g (0.000183 mole) of 4-amino-3-methylbenzoic acid, 1 mL of ethanol, 4 mL of water and 4 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 0.029 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methylbenzoic acid (I-60) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:16][C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(F)cc2)Cc2ccccc2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.8 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2-indanol (21.0 g, 92.1 mmol) in THF (200 mL) was added a solution of concentrated hydrochloric acid (40 mL) in water (60 mL). The solution was stirred at room temperature overnight (14 h). The solid was collected and washed with pentane (50 mL) and then tetrahydrofuran (50 mL) to give 13.7 g of yield 2-(4-fluorophenyl)-1H-indene. 1H-N.M.R. (CDCl3) d 3.78(br s, 2H), d 7.05 (br d, J=8.6 Hz, 2H), d 7.13(br s, 1H), d 7.17(tt, J=7.4, 1.2 Hz, 1H), d 7.7(br t J=7.4 Hz, 1H), d 7.38(br d, J=7.4Hz, 1H), d 7.45(br d, J=7.4 Hz, 1H), d 7.57(br dd, J=9.0, 5.4 Hz, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:23]>C1(C)C=CC=CC=1>[Cl:23][C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccc2cc(Cl)[nH]c2c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a stirred solution of 6-chloroindolin-2-one 1 (500 mg, 2.99 mmol) in toluene (25 mL) under inert atmosphere were added N,N-dimethylaniline (362 mg, 2.99 mmol) and POCl3 (918 g, 5.98 mmol) at RT; heated to 110° C. and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 10% aq. NaHCO3 solution (30 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 5% EtOAc/Hexanes to afford compound 2 (350 mg, 63%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.09 (br s, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.28 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.39 (s, 1H); MS (ESI): m/z 184 (M−H+)
Reaction SMILES: C(O)C.[C:4]([C:6]1[C:11]2[N:12]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[O:14][C:10]=2[C:9]([CH2:18][C:19](=S)[N:20]([CH3:22])[CH3:21])=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]=1[CH3:30])#[N:5]>[Ni].O1CCCC1>[CH:15]1([C:13]2[O:14][C:10]3[C:11](=[C:6]([C:4]#[N:5])[C:7]([CH3:30])=[C:8]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:9]=3[CH2:18][CH2:19][N:20]([CH3:21])[CH3:22])[N:12]=2)[CH2:16][CH2:17]1
Reactant: Cc1c(-c2ccccc2)c(CC(=S)N(C)C)c2oc(C3CC3)nc2c1C#N
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2ccccc2)c(CCN(C)C)c2oc(C3CC3)nc2c1C#N
Temperature: 50 °C
Reaction time: 5 h
Yield: 46.9 %

Procedure:
Raney nickel (corresponding to 0.2 ml) was added to an ethanol (1 ml)/tetrahydrofuran (1 ml) solution of 2-(4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)-N,N-dimethylethanethioamide (I-314) (14.0 mg, 0.037 mmol), followed by stirring in an oil bath at 50° C. for 5 hours. The reaction liquid was filtered, the filtrate was concentrated, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (6.00 mg, 47%) as a white solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][CH:12]=[CH:13][C:14]([O:16]CC)=[O:15])=[CH:4][C:3]=2[O:2]1.[OH-].[Na+].O.Cl>CO.O.CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C=CC=Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C=CC=Cc1ccc2c(c1)OCO2
Yield: 90.9 %

Procedure:
To a solution of 6.8 g (27.6 mmol) of the ester compound prepared above in methanol (20 ml) was added in an argon atmosphere a solution of 11.0 g (275 mmol) of sodium hydroxide in water - methanol (1 : 6, 280 ml). The mixture was reacted at room temperature for 4.5 hours. Water was added to the reaction solution, followed by adjustment of the pH with 6N-hydrochloric acid to 3. Crystals then precipitated were isolated by filtration. There was obtained 5.478 g (25.1 mmol) of 5-(3,4-methylenedioxyphenyl)-2,4-pentadienic acid.