Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[CH2:12]([NH2:16])[CH:13]([NH2:15])[CH3:14]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:16][CH2:12][CH:13]([NH2:15])[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(N)CN
Solvent: O
Product: CC(N)CNc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 92.9 %

Procedure:
2.8 g of 4-nitrofluorobenzene were heated to 80° C. in 29.6 g of propylenediamine and then stirred for 1 hour at the same temperature. The reaction mixture was poured into water and precipitated crystals were collected by filtration, thereby obtaining 3.6 g of N-(4-nitrophenyl)propylenediamine as crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:11][C:10]=1[C:18]1[N:22]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH3:32])[CH:27]=[CH:26]3)[C:21](=[O:33])[NH:20][N:19]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:11][C:10]=1[C:18]1[N:22]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH3:32])[CH:27]=[CH:26]3)[C:21](=[O:33])[NH:20][N:19]=1
Reactant: Cn1ccc2cc(-n3c(-c4ccc(CCO)cc4OCc4ccccc4)n[nH]c3=O)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1ccc2cc(-n3c(-c4ccc(CCO)cc4O)n[nH]c3=O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
The protected triazolone (4) (150 mg, 0.34 mmol) was dissolved in EtOAc (2 ml) and MeoH (2 mL) then palladium (100 mg, 10% on activated carbon) was added. The reaction was stirred under an atmosphere of hydrogen (balloon) at room temperature for 18 h. Filtration through a silcagel plug followed by removal of solvent under reduced pressure produced the desired product as a white solid (100 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH2:25][CH3:26])[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.[Cu][C:28]#[N:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH2:25][CH3:26])[C:18]1[CH:23]=[CH:22][C:21]([C:28]#[N:29])=[CH:20][CH:19]=1
Reactant: CCC1(c2ccc(Br)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CCC1(c2ccc(C#N)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Temperature: 200 °C

Procedure:
To a solution of 0.062 g (0.14 mmol) 6-chloro-4-ethyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 1 mL DMF was added 0.015 g (0.17 mmol) copper(I) cyanide and the mixture heated in a sealed tube at 200° C. for 2 hours. After cooling to room temperature, the mixture was filtered and the resulting DMF solution purified by preperative reverse phase chromatography (linear gradient 5 to 95% CH3CN/H2O over 30 min, 0.05% added TFA, C18 SunFire 19×150 mm) to provide 6-chloro-4-ethyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) δ 8.06 (s, NH); 7.71 (br d, 2H, J=8.24 Hz); 7.55 (br d, 2H, J=8.43 Hz); 7.14 (dd, 1H, J=8.61 and 2.20 Hz); 6.69 (d, 1H, J=8.61 Hz); 6.43 (d, 1H, J=2.02 Hz); 3.78 (dq, 1H, J=8.97 and 18 Hz); 3.60 (dq, 1H, J=8.43 and 17 Hz); 2.44 (dq, 1H, J=7.15 and 14 Hz); 2.27 (dq, 1H, J=7.14 and 14 Hz); 0.93 (t, J=7.15 Hz, 3H); MS (Electrospray): exact mass calculated for C19H15ClF3N3O+H 394.0929 found 394.0937
Reaction SMILES: C[O:2][C:3]([C:5]1[O:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[C:6]=1[O:23][CH3:24])=[O:4].[OH-].[Na+].O>CO>[CH3:24][O:23][C:6]1[C:7]2[N:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[O:16][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1oc2c3ccccc3n(-c3ccccc3)c2c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C(=O)O)oc2c3ccccc3n(-c3ccccc3)c12
Yield: 45 %

Procedure:
A suspension of 13.5 g (0.042 mole) of 3-methoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxylic acid methyl ester in 75 ml of methanol was treated with 70.6 ml of 1.0N aqueous sodium hydroxide. The mixture was stirred at reflux for 17 hours, then added to 1.4 l of water. The insoluble material was filtered, added to 1.0 l of water, and acidified with acetic acid while cooling in an ice bath. The crude acid product was recovered by filtration. The original filtrate from the reaction mixture and 1.4 l of water was also cooled in ice and acidified with acetic acid. The crude product obtained was filtered and combined with the earlier crop. The combined crude products were stirred in 400 ml of water, filtered, and recrystallized from methanol. There are obtained 5.8 g (45% yield) of analytically pure acid, mp 154°-155° C.
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[CH:6][NH+:5]=1.[F:15][C:16]1([F:29])[O:28][C:19]2=[CH:20][C:21]3[NH:25][C:24]([SH:26])=[N:23][C:22]=3[CH:27]=[C:18]2[O:17]1.O>C(O)C.[OH-].[Na+]>[F:29][C:16]1([F:15])[O:28][C:19]2=[CH:20][C:21]3[NH:25][C:24]([S:26][CH2:3][C:4]4[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[CH:6][N:5]=4)=[N:23][C:22]=3[CH:27]=[C:18]2[O:17]1
Reactant: COc1c[nH+]c(CCl)c(C)c1OC
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c(C)c1OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.96 g of 2-chloromethyl-4,5-dimethoxy-3-methylpyridinium chloride are added to a solution of 0.92 g of 2,2-difluoro-5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol in 10 ml of ethanol and 10 ml of 1N sodium hydroxide solution. The yellow reaction mixture is stirred at 20° C. for 1 hour, a further 10 ml of water are added, whereupon a colorless solid precipitates out, the mixture is stirred for a further 5 hours and filtered and the residue is rinsed with 1N sodium hydroxide solution and water and dried to constant weight. The amorphous powder is recrystallized from methylene chloride/diisopropyl ether. 1.5 g (93% of theory) of the title compound are obtained in the form of colorless crystals of m.p. 160°-161° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38](Br)[CH:39]([CH3:41])[CH3:40]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)CBr
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)Cn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and isobutyl bromide (0.326 mL) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-methylpropyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 19, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-methylpropyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.11 g) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][Br:14])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C#CC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C#Cc1ccc(CBr)cc1

Procedure:
3.35 g of 4-(3,3-Dimethyl-1-butynyl)toluene, 3.47 g of N-bromosuccinimide and 100 mg of dibenzoylperoxide in 50 ml of carbon tetrachloride are refluxed for 8 hours. The mixture is filtered and the solvent removed under vacuum. The pure product is obtained as an oil following chromatography over silica gel using hexane as an eluant.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:17])=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Product: O=C(NCCCOc1cccc(CN2CCCCC2)c1)NNC(=O)Nc1ccc(Cl)cc1

Procedure:
The compound is prepared by a method analogous to that of Example 20 from N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carboxamide and 4-chlorophenyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]1[O:12][C@@H:11]2[C@@H](O)C[O:15][C@@H:10]2[C@@H:9]1[OH:17].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:6][C:5]([O:4][C@@H:1]1[C@H:11]2[O:12][CH2:8][C@@H:9]([OH:17])[C@H:10]2[O:15][CH2:2]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O

Procedure:
At approx. 100° C., 102 g (1 mol) of acetic acid anhydride are added to 146 g (1 mol) of isosorbide and 1 g of sodium acetate. This mixture is heated for half an hour under reflux and the acetic acid formed is then removed under a water-pump vacuum up to a sump temperature of approx. 140° C. An analysis of the residue shows that isosorbide, isosorbide-2-acetate, isosorbide-5-acetate and isosorbide-2,5-diacetate are present in approximately equal proportions. By the following transacylation and distillation, according to example 1, 182 g of raw isosorbide-2-acetate are obtained. After recrystallizing from 200 ml of acetone 92 g of pure isosorbide-2-acetate with a M.P. of 80° C. are obtained. The residue (90 g) remaining after concentrating the filtrate is again subjected to transacylation after adding 0.5 g of sodium acetate whereby again an almost quantitative yield of raw isosorbide-2-acetate is achieved. From this, 43 g of pure isosorbide-2-acetate and 46 g residue are obtained as described above. By another distillation in the presence of sodium acetate it is possible to prepare from the 46 g residue, 44 g of raw isosorbide-2-acetate from which, by recrystallisation, 26 g of pure isosorbide-2-acetate can be isolated. In this way a total amount of 161 g of pure isosorbide-2-acetate is obtained corresponding to 83% of the theory and 18 g residue which may be used for further transacylations. By repeating the above mentioned procedure resp. by adding the remaining residue to the next acylation batch an almost quantitative yield of pure isosorbide-2-acetate can be obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:14][CH2:12][C:10]1[C:9]([F:13])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1cc(F)c(C)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)c(CBr)cc1F
Temperature: 88 °C
Reaction time: 18 h
Yield: 37.1 %

Procedure:
To methyl 2,5-difluoro-4-methylbenzoate (Preparation 26, 55 g, 0.29 mol) in carbon tetrachloride (0.4 L) was added N-bromosuccinimide (52.6 g, 0.29 mol) and dibenzoyl peroxide (1 g, 3.5 mmol) and heated at 88° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and allowed to stand for 18 hours, then washed with water (400 mL), brine (100 mL), dried over sodium sulphate and concentrated in vacuo. The resulting solid was triturated with n-heptane (120 mL) and recrystallised from hot n-heptane (50 mL) to yield the title compound as a pale yellow solid (28.5 g, 36%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20])(=[O:13])=[O:12]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccccc12
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccccc12
Yield: 26 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 11) (25 mg, 0.10 mmol) and 3-aminobenzoic acid (28 mg, 0.20 mmol) using a modified reaction time (4 hours) and a modified reaction temperature (60° C.). The title compound was obtained in 26% yield (8.9 mg). MS (ESI+) calcd mass for C16H13NO4S2 347.028599, found 347.028659.
Reaction SMILES: O.[CH3:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:16][CH2:15][CH2:14][S:13]1(=[O:18])=[O:17]>O1CCCC1>[CH3:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:16][CH2:15][CH2:14][S:13]1(=[O:18])=[O:17]
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCCS1(=O)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N)ccc1N1CCCS1(=O)=O

Procedure:
1.0 g of water-moist Raney nickel is added to a solution of 2.50 g (9.76 mmol) of 2-(2-methyl-4-nitrophenyl)isothiazolidine 1,1-dioxide in 50 ml of tetrahydrofuran, and the mixture is hydrogenated at room temperature. The catalyst is filtered off, and the filtrate is evaporated, giving 2-(2-methyl-4-aminophenyl)isothiazolidine 1,1-dioxide as a yellowish solid; ESI 227.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C:6](=[O:10])[C:7]([C:8]#[N:9])=[CH:17][N:18]([CH3:19])[CH3:20]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)NCc1ccccc1Cl
Product: CN(C)C=C(C#N)C(=O)NCc1ccccc1Cl

Procedure:
As for Example 1, N-o-chlorobenzyl-2-cyanoacetamide, colorless needles, m.p. 108°-109° C., (prepared as described in U.S. Pat. No. 3,116,312) is heated with N,N-dimethylformamide dimethylacetal to give N-o-chlorobenzyl-2-cyano-3-dimethylaminoacrylamide as colorless needles, m.p. 144°-146.5° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1
Reactant: NC(CC(=O)O)c1cncc(Br)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 52 %

Procedure:
9.54 g (38.93 mmol) 3-amino-3-(5-bromopyridin-3-yl)propionic acid were suspended in 158 ml methanol and the mixture cooled to 0° C. 4.26 ml (58.39 mmol) thionyl chloride were slowly added. The mixture was stirred at room temperature for 20 hours and concentrated. The residue was treated with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic part was dried with sodium sulfate and concentrated. Chromatography over silica gel (dichloromethane/ethanol 100/0-50/50) gave 5.84 g (52%) 3-amino-3-(5-bromopyridin-3-yl)-propionic acid methyl ester.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:26])[CH3:25].O>>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)cc1
Reactant: CC(=O)Cl
Solvent: O
Product: CC(=O)Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 4-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl-1-butynyl]benzenamine (Example 14) and acetyl chloride, containing 0.1 mol of water; mp 172°-173.4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.C([Li])CCC.[CH:17](=[O:19])[CH3:18]>O1CCCC1.O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([CH:17]([OH:19])[CH3:18])[O:9][C:8]=12
Reactant: COc1nccc2ccoc12
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nccc2cc(C(C)O)oc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 7-methoxyfuro[2,3-c]pyridine (1.5 g) in dry tetrahydrofuran (50 ml) was stirred at −78° C. under dry nitrogen. n-Butyllithium (1.6N solution in hexanes, 6.9 ml) was added dropwise and the resulting solution stirred at −78° C. for 60 minutes. Acetaldehyde (5.7 ml) was added and stirring continued at −78° C. for 90 minutes before warming to room temperature. The mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave the title compound (1.8 g) as a brown oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[Na+]>O>[C:1]1([C:7]2[CH:12]=[C:11]([OH:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc(-c2ccccc2)c1
Temperature: 95 °C
Reaction time: 0.17 h

Procedure:
To a 100 ml. beaker, 25 g. of the starting phenylphenol mixture used in Example 1, above, and water containing 1.0 g. of sodium hydroxide were added. The mixture was heated to 95° C. and stirred for 10 minutes after reaching this temperature. This gave a mole ratio of caustic to m-phenylphenol of about 5.55 to 1. Water was added to maintain volume. The solid was collected on a filter. The cake was treated with small amounts of hydrochloric acid and dried. The resulting p-phenylphenol was analyzed and shown to have 1.2% of m-phenylphenol present therein.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(Cl)Cl.CN.[C:17]([BH3-])#[N:18].[Na+]>C(O)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:18][CH3:17])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC1CCC2(CC1)OCCO2
Reaction time: 8 h
Yield: 43.8 %

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decan-8-one (3.1 g, 20 mmol) and CH2Cl2 (50 mL) was stirred with methylamine (15 mL, 30 mmol, 2.0M solution in THF), sodium cyanoborohydride (1.3 g, 20 mmol), and acetic acid (0.1 mL) at room temperature. After 8 hours, the reaction mixture was washed with water (50 mL) and concentrated. The residue was purified by flash chromatography to afford 1.5 g of (1,4-dioxa-spiro[4.5]dec-8-yl)-methyl-amine as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8](=[O:29])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[C:11]([NH:17][C:18](=O)[CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:10]=1>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:9]1[CH:14]=[CH:13][C:12]2[N:15]([CH3:16])[C:18]([CH2:19][NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[N:17][C:11]=2[CH:10]=1)=[O:29]
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(NC(=O)CNC(=O)OC(C)(C)C)c1)c1ccccn1
Solvent: CC(=O)O
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNC(=O)OC(C)(C)C)n2C)c1ccccn1

Procedure:
10.0 g (0.02 mol) of 3-[(N-tert.butoxycarbonyl-amino)acetylamino]-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide were dissolved in 50 ml of glacial acetic acid and refluxed for one hour. Then the solvent was distilled off, the residue was mixed with ice water and adjusted to pH 8 by the addition of 2N ammonia. After extraction three times with ethyl acetate the combined organic phases were washed with saline solution and dried over sodium sulphate. After evaporation of the solvent the crude product was chromatographed on silica gel, eluting first with methylene chloride, then with methylene chloride/ethanol (50:1) and (25:1). The desired fractions were combined and evaporated down. Yield: 5.85 g (61% of theory), C25H31N5O5 (481.6) Rf value: 0.70 (silica gel; methylene chloride/ethanol=9:1)
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)=O.O.[NH2:15]N>>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:12]=[N:11][CH:10]=[CH:9][N:8]=2)=[N:15]1
Reactant: CN(C)C=CC(=O)c1cnccn1
Reactant: NN
Solvent: O
Product: c1cnc(-c2cc[nH]n2)cn1

Procedure:
A mixture of 496 mg of 3-dimethylamino-1-(2-pyrazinyl)-2-propen-1-one and 10 ml of hydrazine hydrate was heated at 90°-100° C. for 16 hours, then allowed to cool, giving 210 mg of 1H-pyrazol-3-yl-pyrazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C@@:9]([OH:19])([C:14]#[C:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([F:13])([F:12])[F:11].Cl[C:21]([O-])=[O:22]>>[CH:6]1[C:5]([Cl:8])=[CH:4][C:3]2[C@:9]([C:10]([F:13])([F:11])[F:12])([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)[O:19][C:21]([NH:1][C:2]=2[CH:7]=1)=[O:22]
Reactant: O=C([O-])Cl
Reactant: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1

Procedure:
This intermediate, (2S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol, as a free base, is reacted with a chloroformate derivative in basic conditions to give, after 1 to 6 hours reaction, an alkyl carbamate intermediate (reaction of the amine moiety of intermediate (II) with the chloroformate derivative) that is then cyclized to yield Efavirenz.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:15]([N-]C(C)C)(C)C.[Li+]>>[Cl:1][C:2]1[N:12]=[C:11]([Cl:13])[C:10]([F:14])=[C:9]([CH3:15])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Agent: [Li+]
Product: CCOC(=O)c1c(Cl)nc(Cl)c(F)c1C

Procedure:
Ethyl 2,6-dichloro-5-fluoronicotinate (Chem. Pharm. Bull. 35(6), 2280 (1987)) was treated with lithium diisopropylamide and quenched with methyl iodide to give, upon work-up, ethyl 2,6-dichloro-5-fluoro-4-methylnicotinate. This material was hydrolyzed to give the corresponding acid which was elaborated in the usual manner to give 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid. 7-chloro-1-cyclopropyl-5-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was synthesized in the same manner.