Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)=[O:14])=[CH:11][CH:10]=1)([CH3:8])[CH3:7]>>[CH:6]([C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:14])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:19])[C:24]=2[CH:25]=1)([CH3:7])[CH3:8]
Reactant: CC(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CC(C)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 95 °C

Procedure:
Fuming sulfuric acid (25 mL, 30%) was added to 8.5 g (32 mmol) of 2-(4'isopropylbenzoyl)benzoic acid. The mixture was then heated to 95° C. for 1 h in a water bath. The resultant dark solution was poured cautiously over crushed ice to yield a beige solid which was extracted with chloroform. The chloroform layer was washed sever-al times with a dilute NaOH solution ≈10%), followed by a dilute HCl solution and finally with deionized water. The resultant yellow chloroform solution was dried with MgSO4, filtered and the chloroform was removed under vacuum to yield a yellow/orange solid. The product was recrystallized from heptane to yield a yellow product. (1.00 g, 113%), mp 53-54° C.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[N:13]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][N:15]=[N:14]1>>[N:13]1([CH2:18][CH2:19][NH:20][C:9]([C:5]2[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=2[CH3:8])=[O:11])[CH:17]=[CH:16][N:15]=[N:14]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: NCCn1ccnn1
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Yield: 97.6 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2 g, 11.96 mmol) reacted with 2-[1,2,3]triazol-1-yl-ethylamine (2.66 g, 14.36 mmol) to give 3.05 g (98%)of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O.C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([OH:19])[CH3:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1
Reactant: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(O)c1ccc(Oc2ccc(N)cn2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 2.7 %

Procedure:
8.14 g of 1-{4-[(5-nitro-2-pyridinyl)oxy]phenyl}-1-ethanone was dissolved in 15 ml of ethyl acetate and, after adding 2 g of 10% palladium-carbon, the mixture was stirred at 0° C. under partial hydrogen pressure overnight. After the completion of the reaction, the reaction solution was filtered with celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography. The compound synthesized in Reference Example 24 was obtained from a fraction prepared by using an eluent (ethyl acetate/n-hexane (2:1)), whereas, the titled compound (193 mg) was obtained from a fraction prepared by using an eluent (ethyl acetate/n-hexane (3:1)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:34])[C:15](=[O:33])[C:16]2[CH:21]=[C:20]([S:22]CC[Si](C)(C)C)[CH:19]=[C:18]([C:29](F)(F)F)[CH:17]=2)=[C:4]([O:35][CH3:36])[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CCOC(C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:34])[C:15](=[O:33])[C:16]2[CH:17]=[C:18]([CH3:29])[CH:19]=[C:20]([SH:22])[CH:21]=2)=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCC[Si](C)(C)C)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C)cc(S)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-3-(trifluoromethyl)-5-(2-(trimethylsilyl)ethylthio)benzamide (0.711 g, 1.32 mmol) in THF (12.6 mL) was added tetrabutylammonium fluoride (1M solution in THF, 6.96 mL, 6.96 mmol) and the clear light yellow solution was stirred at room temperature for 90 minutes. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system eluting with a gradient of CH2Cl2:MeOH (100:0 to 90:10). Colorless solid (0.41 g; 63%). MS (ESI): m/z=437.09 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH3:12]>ClCCl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH2:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Solvent: ClCCl
Product: Cc1ccc(S(N)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
To a solution containing 4-toluenesulfonyl chloride (10 g, 52.45 mmol) in dichloromethane (100 mL) at -78° C., liquid ammonia (20 mL) was added. After the mixture was stirred at -78° C. for 4 h, precipitates were removed by filtration and the filtrate was concentrated in vacuo to remove the solvent. The residue was then recrystallized from n-hexane/ethyl acetate (v/v=2:5) to give 7.77 g (85.7%) of 4-toluenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:12]1([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:14][CH2:13]1>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:12]3[CH2:13][CH2:14]3)[CH2:21][CH2:20]2)[N:28]=1)=[O:5]
Reactant: Nc1cccc(OC2CCN(CC3CC3)CC2)n1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(OC2CCN(CC3CC3)CC2)n1)c1ccc(F)cc1Cl
Reaction time: 15 h
Yield: 79.4 %

Procedure:
Add 2-chloro-4-fluorobenzoyl chloride (149 mg, 0.58 mmol) to a solution of 6-(1-cyclopropylmethyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 70, 130 mg, 0.53 mmol) in pyridine (7 mL) and beat at 55° C. for 15 hr. Remove pyridine in vacuo, dissolve the residue in CH2Cl2, wash with saturated NaHCO3 solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 5% 2M NH3-Methanol in CH2Cl2) provides 170 mg (79%) of the title compound: mass spectrum (ion spray): 404.1 (M+1); 1H NMR (CDCl3, ppm): 8.08 (s, 1H), 7.63 (m, 2H), 7.52 (t, 1H), 7.11 (m, 1H), 6.99 (m, 1H), 6.41 (d, 1H), 4.82 (m, 1H), 2.72 (m, 2H), 2.26 (m, 2H), 2.17 (d, 2H), 1.89 (m, 2H), 1.69 (m, 2H), 0.77 (m, 1H), 0.40 (m, 2H), 0.00 (m, 2H). Hydrochloride salt: Analytical calc. for C21H23ClFN3O2.HCl.0.5H2O: C, 56.13; H, 5.61; N, 9.35. Found: C, 56.12; H, 5.30; N, 9.35.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[NH:13][C:14]1[N:15]=[CH:16][C:17]2[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[O:24])[CH2:20][C:18]=2[N:19]=1>CN(C)C=O.ClCCl.O.[Cl-].[Li+]>[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[NH:13][C:14]1[N:15]=[CH:16][C:17]2[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][C:1]#[N:2])=[O:24])[CH2:20][C:18]=2[N:19]=1
Reactant: [C-]#N
Reactant: O=C(OCCCCl)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCCCOC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 100 °C
Yield: 87.6 %

Procedure:
Add sodium cyanide (0.230 g; 1.5 equiv; 4.69 mmoles) to a solution containing 3-chloropropyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (1.15 g; 1.0 equiv; 3.08 mmoles) in dimethylformamide (10 mL). Heat the reaction mixture to 100° C. for 3 hours, then cool to ambient temperature, dilute with dichloromethane, water, and 5% lithium chloride solution. Separate the layers and further extract the aqueous layer with dichloromethane and ethyl acetate. Dry the combined organic extracts over sodium sulfate, filter, and concentrate to provide 3-cyanopropyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (0.98 g; 87%) as a brown solid: MS (m/z): 364(M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([NH:28][C:29]([C:31]2[CH:32]=[C:33]([C:43]([CH3:46])=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][C:37]([C:40]([OH:42])=O)=[CH:36][CH:35]=2)=[O:30])[CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1.[NH2:57][CH2:58][C:59]([NH:61][CH3:62])=[O:60].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([NH:28][C:29]([C:31]2[CH:32]=[C:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([NH:57][CH2:58][C:59]([NH:61][CH3:62])=[O:60])=[O:42])=[CH:36][CH:35]=3)[C:43]([CH3:46])=[CH:44][CH:45]=2)=[O:30])[CH2:27][CH2:26]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cc1
Reactant: CNC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CNC(=O)c1ccc(-c2cc(C(=O)NC3CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HATU (65 mg, 0.17 mmol) was added to a solution of {3′-[(cyclopropylamino)carbonyl}-6′-methyl-biphen-4-yl}carboxylic acid (50 mg, 0.17 mmol) in DMF (2 ml). After 5 minutes HOBT (23 mg, 0.17 mmol), 2-amino-N-methylacetamide (0.17 mmol) and DIPEA (0.087 ml, 0.51 mmol) were added and the reaction mixture stirred at room temperature under nitrogen for 18 hours. The DMF was removed in vacuo and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate solution (1M, 5 ml). The organic phase was purified by SPE cartridge (Si, 5 g) eluting in turn with DCM, chloroform, ether, ethyl acetate, acetonitrile, acetone, ethanol, DCM:ethanol:ammonia (40:8:1, 20:8:1 and 10:8:1). The product fractions were concentrated in vacuo to give N3-cyclopropyl-N4′{[(methylamino)carbonyl]methyl}-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@@H:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=2)=[O:30])[C:3]1=[O:20]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methylphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give analytical product: m.p. 208°-210° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13](=[O:20])[NH:12][C:11]1=[O:21])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[C:13](=[O:20])[NH:12][C:11]1=[O:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(=O)n(CCCO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A solution of 1-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-5-trifluoromethyl-1H-pyrimidine-2, 4-dione (Prep 19, 0.86 g, 2.4 mmol) in DCM (10 mL) was cooled at 0° C. and then TFA (2.8 mL, 36 mmol) was added. The mixture was stirred for 1 hour at room temperature and then the solvent was evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (7-3) to afford the title compound (0.33 g, 57% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[C:1]1([CH:7]2[C:8](=[O:9])[N:10]3[CH:15]2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C(=O)N1CCCCC1)c1ccccc1
Solvent: O
Product: O=C1C(c2ccccc2)C2CCCCN12

Procedure:
contacting a solution of 1-(phenylglyoxylyl)piperidine arenesulfonylhydrazone in a water immiscible organic solvent with an inorganic base, in the presence of phase transfer catalyst to obtain 7-phenyl-1-azabicyclo[4.2.0]octan-8-one;
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:16][C:15](=[O:17])[CH2:14][CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]1>ClCCl.C(N(CC)CC)C>[C:1]([O:17][C:15]1[CH2:14][CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][C:11](=[O:10])[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CC(=O)CC(=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(=O)C=C(OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.75 g (55.1 mmol) Benzoyl chloride was added dropwise to 10.00 g (54.3 mmol) ethyl 3,5-dioxocyclohexanecarboxylate, dissolved in 100 ml dichloromethane and 15 ml triethylamine, at 10° C. The mixture was stirred for 3 hours at room temperature, poured into ice, separated, the organic phase shaken with 1N hydrochloric acid, saturated sodium bicarbonate and water, dried (magnesium sulphate) and concentrated. The ethyl 3-benzoyloxy-5-oxo-3-cyclohexenecarboxylate, so obtained, was dissolved in 75 ml acetonitrile and after addition of 15 ml triethylamine and 1.5 ml 2-hydroxyisobutyronitrile, was stirred at 24 hours at room temperature. The mixture was taken up in 100 ml diethyl ether and extracted with 100 ml 2N hydrochloric acid and then twice with, each time, 50 ml 5% potassium carbonate solution. After covering the aqueous phase with a layer of 100 ml diethyl ether, it was acidified with 4N hydrochloric acid until it was pH 3, separated, washed with water, dried (magnesium sulphate) and evaporated on a rotary evaporator. It was purified by recrystallising from hexane.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8](F)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([NH2:22])C1C=CC=CC=1>C1C=CC=CC=1>[NH2:22][C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[C:11]([F:12])=[C:10]([F:13])[CH:9]=1
Reactant: COC(=O)c1c(F)cc(F)c(F)c1F
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1c(N)cc(F)c(F)c1F
Reaction time: 1.5 h

Procedure:
60 g of methyl 2,3,4,6-tetrafluorobenzoate and 70 g of benzylamine were reacted under reflux for 1 hour in 400 ml of benzene. After the reaction mixture was allowed to cool down, it was washed successively with water, 1% hydrochloric acid and 1% aq. sodium carbonate, each in the amount of 600 ml. The reaction mixture was treated with anhydrous magnesium sulfate and then concentrated. Crystals thus precipitated were collected by filtration and thereafter washed with methanol. 30 g of the crystals and about 2 ml of palladium/carbon were added to a liquid mixture which consisted of 100 ml of acetic acid and 200 ml of methanol. The resultant mixture was hydrogenated for 1.5 hours. The catalyst was filtered off and the filtrate was concentrated, whereby methyl 6-amino-2,3,4-trifluorobenzoate was obtained as a crystalline residue.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C@H:15]1[C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][N:16]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:5])=[O:4])[CH3:2].[H][H]>CO.C1COCC1.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:7]([C@H:15]2[C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][N:16]2[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH:8]=1
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)CC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)CC
Yield: 102.2 %

Procedure:
To 35E (2.2 g) in methanol (50 mL) and THF (30 mL) was added 10% Pd/C (700 mg). The mixture was hydrogenated with a hydrogen balloon for 6.0 h. The Pd/C was removed by filtration and the filtrate was concentrated to afford 35G (2.1 g, 95% yield). 1H NMR (500 MHz, DMSO-d6, 100° C.) δ ppm 1.13 (t, J=7.42 Hz, 3H) 1.16-1.23 (t, J=7.42 Hz, 3H) 1.31 (s, 9H) 1.93-2.01 (m, 1H) 2.17 (m, 1 H) 2.78 (br s, 1H) 3.14 (br s, 2H) 3.38-3.47 (m, 1H) 3.66 (t, J=8.52 Hz, 1H) 4.10 (q, J=7.42 Hz, 2H) 5.60 (s, 1H) 5.83 (br s, 1H) 6.51-6.58 (m, 2H) 7.49 (d, J=9.34 Hz, 1H); LC-MS 427 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH3:11].CO>CO>[NH2:11][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1
Reactant: N
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CO
Product: N#Cc1cnc(N)nc1Cl
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a stirred solution of 2,4-dichloropyrimidine-5-carbonitrile (500 mg, 2.87 mmol) in MeOH (5 mL) was added 2M NH3/MeOH (5 mL). After stirring for 20 min the resulting precipitate was filtered and washed with MeOH to afford the title compound as a white solid (173 mg, 39%). LCMS (Method C): RT 1.91 min [M+H]+ 155.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.68 (1H, s), 8.23 (2H, br s)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[C:12]([S:16][CH2:17][C:18](=O)[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])([CH3:15])([CH3:14])[CH3:13]>CC(O)(C)C>[C:12]([S:16][C:17]1[C:8]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:9]=2)[NH:10][C:18]=1[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: COC(=O)C(C)(C)Cc1[nH]c2ccc(OC)cc2c1SC(C)(C)C
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A mixture containing 4-methoxyphenyl hydrazine HCl (70.66 g, 0.405 mol) and methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate (99.54 g 0.405 mol) in tBuOH (400 ml) was heated at a gentle reflux for 48 hours. The mixture was allowed to cool to RT and the precipitated NH4Cl was removed by filtration. The residue was concentrated and fractionated on a plug of silica using EtOAc/hexane (1:3) as eluent. Evaporation of the appropriate fraction gave an orange-brown solid which was crystallized from EtOH (100 ml). Yield from two crops afforded 55.6 g of the title compound.
Reaction SMILES: C(O[SiH](OCC)OCC)C.[C:11]1([CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1COCC1.[OH-].[Na+]>CC(C)[O-].[Nd+3].CC(C)[O-].CC(C)[O-].CCOCC.O>[C:11]1([CH2:17][CH2:18][CH:19]([OH:21])[CH3:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CCc1ccccc1
Agent: CC(C)[O-]
Agent: CCO[SiH](OCC)OCC
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)CCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
A dry Schlenk tube under argon was charged with 48 mg (0.15 mmol) of neodymium (III) isopropoxide. Triethoxysilane (1.4 mL, 7.5 mmol) was added, and the reaction mixture was heated to 60° C. After 0.5 hours, 4-phenyl-2-butanone (450 μL, 3 mmol) was added. After 24 hours, the reaction was complete, as determined by GLC analysis of a aliquot taken from the reaction mixture. THF (8 mL) and aqueous NaOH (1 N, 15 mL) were added, and the mixture was stirred vigorously for 12 hours. The mixture was added to water and ether (50 mL of each), shaken vigorously, and separated. The aqueous layer was then extracted with an additional 50 mL of ether, and the combined organic layers were dried over MgSO4. After removal of the drying agent by filtration and concentration of the solution by rotary evaporation, the crude material was purified by flash chromatography (ether:hexane=3:7) to afford 245 mg (54% yield) of 4-phenyl-2-butanol (>95% pure by 1H-NMR analysis).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:26]([NH:25][C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)=[O:27])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Yield: 51.2 %

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (0.89 g, 3.6 mmol) and 4-fluorophenyl isocyanate (409 μL, 3.6 mmol) in THF (20 mL) are reacted according to method C yielding 0.71 g of the product as a colorless solid after column chromatography with hexane-EtOAc.
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18]CC)=[O:17])(=O)C.C(=O)([O-])[O-].[Ca+2].BrBr>C(Cl)(Cl)(Cl)Cl.CN(C)C(=O)C.C(Cl)(Cl)Cl.O>[C:16]([CH2:15][C:14]([CH3:22])([CH3:21])[CH2:13][CH2:12][CH2:11][CH2:10][C:6]1[C:5](=[O:4])[CH2:9][CH2:8][CH:7]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)CC(C)(C)CCCCC1=C(OC(C)=O)CCC1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CCCCC1=CCCC1=O)CC(=O)O

Procedure:
To a rapidly stirred mixture of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene (35 g., 0.113 mole) chloroform (95 ml.), water (125 ml.) and calcium carbonate (11.8 g.) cooled in an ice-bath is added dropwise over a period of thirty minutes a solution of bromine (18.8 g.) in carbon tetrachloride (31 ml.). After stirring in the cold for an additional 45 minutes the orange colored chloroform layer is separated and washed with dilute sodium bisulfite and saturated saline solution, dried over magnesium sulfate and taken to dryness in vacuo (bath temperature: 35°-40°) leaving an amber colored oil. A slurry of 100 ml. of N,N-dimethylacetamide and 16.5 g. of CaCO3 is stirred and heated to reflux under nitrogen flow. The above dried oil is added from a dropping funnel rapidly, maintaining reflux and nitrogen flow for thirty minutes. The cooled reaction mixture is filtered, and the precipitate is washed with ether. The filtrate is poured into two liters ice-cold water and is extracted with ether. The combined extracts and washing in washed with water, saturated saline, treated with decolorizing charcoal, filtered. The solvent evaporated in vacuo to give 24 g. (77%) of subject product.