Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:26])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:25])([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:6][CH2:5]2.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][C:2]1[C:3]([CH3:26])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:25])([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:6][CH2:5]2)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Temperature: 0 °C

Procedure:
20.4 g of 6-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman were dissolved in 60 ml of pyridine, and, while stirring, 30 ml of acetic anhydride were added dropwise at 10° C. The mixture was gradually restored to room temperature and then reacted for 1 hour at 30° C. The reaction mixture was cooled and then poured into ice-water and extracted with a 1:1 by volume mixture of benzene and cyclohexane. The extract was washed well with a 2% w/v aqueous solution of hydrochloric acid and then with water, after which it was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, giving the desired 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman. Rf value on thin layer chromatography: 0.64 [silica gel; developing solvent; benzene and ethyl acetate=10:1 by volume]
Reaction SMILES: Br.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:24][CH2:23][N:22](C(N)=O)[CH2:21][CH2:20]3)=[N:11]2)=[CH:6][CH:5]=1.OS(O)(=O)=O.[OH-].[Na+]>O>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: NC(=O)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Agent: Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Yield: 91.8 %

Procedure:
A stirred mixture of 4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 77 (15 g 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 13 g (93%) of 1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred suspension of the indazole (4.0 g, 0.012 moles) in toluene (60 ml) was added phenyl isocyanate (1.38 ml, 0.013 moles). The reaction temperature rose to 35° C. and the product precipitated from the solution. The product was collected and recrystallized twice from toluene to yield 3.57 g (66%) of N-phenyl-4-[1-(4-trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide, m.p. 190°-192 ° C.
Reaction SMILES: [N+:1]([C:4]([C:15](=O)[CH3:16])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([O-:3])=[O:2].[NH2:18][C:19]([CH3:24])=[CH:20][N+:21]([O-:23])=[O:22]>C(O)C>[CH3:16][C:15]1[NH:18][C:19]([CH3:24])=[C:20]([N+:21]([O-:23])=[O:22])[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)[N+](=O)[O-]
Reactant: CC(N)=C[N+](=O)[O-]
Solvent: CCO
Product: CC1=C([N+](=O)[O-])C(c2cccc([N+](=O)[O-])c2)C([N+](=O)[O-])=C(C)N1

Procedure:
23.6 g (0.1 mol) of 2-nitro-1-(3nitrophenyl)-but-1-ene-3-one and 10.2 g (0.1 mol) of 2-amino-1-nitro-prop-1-ene in 150 ml of ethanol were heated under reflux for 12 hours. After the mixture had cooled, the solvent was distilled off in vacuo, and the oily residue was taken up in chloroform, and was chromatographed on a silica gel column, using chloroform with the addition of methanol. The product formed yellow crystals of melting point 237°-240° C. (decomposition) in isopropanol.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(C2=CCNc3ccnn32)c1
Yield: 24.6 %

Procedure:
To a stirred mixture of 25.0 g of 7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine in 250 ml of glacial acetic acid, at room temperature, under nitrogen was added portionwise 14.92 g of sodium cyanoborohydride. The resultant solution was stirred for 24 hours, and then was evaporated in vacuo to give an oil. The oil was dissolved in chloroform and washed with saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give a semi-solid which was chromatographed on a silica gel column using a mixture of 25% ethyl acetate and 75% hexane as the solvent system. The product fraction was collected and evaporated to give 6.2 g of the desired product as orange crystals, mp 61°-64° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Mg+2].[Cl-].[Cl-].[CH2:12]=[O:13]>C1(C)C=CC=CC=1.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:12]=[O:13])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=Cc1ccc(Br)cc1O
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-bromophenol (100.00 g, 0.576 mol) in a mixture of 600 mL of toluene/acetonitile (2:1) was added MgCl2 (110.6 g, 3.68 mol), paraformaldehyde (40.00 g) and the mixture was maintained at 80° C. for 1.5 h while the by-product was distilled off. A second portion of paraformaldenhyde (40.00 g) was added and the mixture was stirred for 2.5 h at 80° C., and the third portion of paraformaldenhyde (30.6 g) was added and stirred for 2 h at 80° C. The reaction was quenched with cool 2.5 N hydrochloride acid, and the mixture was stirred at room temperature for 1 h to afford a biphasic solution. The aqueous phase was extracted with EtOAc. And the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to afford 4-bromo-2-hydroxybenzaldehyde. 1H-NMR (400 MHz, CDCl3) 11.10 (s, 1H), 9.86 (s, 1H), 7.40˜7.43 (d, J=8.4 Hz, 1H), 7.15˜7.20 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10](=[O:17])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(O[NH2:33])(C2C=CC=CC=2)=O)C=CC=CC=1>>[NH2:33][N:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]1=[O:17]
Reactant: O=c1[nH]nc(-c2ccccc2)c2c1CCCC2
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Product: Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2

Procedure:
4-Phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give the title compound. MS (APCI+) M/Z 242 (M+H)+.
Reaction SMILES: S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:23]#[N:24]>O.C(O)C.CN(C=O)C>[F:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]2[NH:28][C:27]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[N:19]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2[nH]c(-c3ccc(F)cc3)nc2c1
Reaction time: 8 h
Yield: 70 %

Procedure:
Sodium metabisulfite (1.66 g, 8.73 mmol) in 10 ml of water was added to 4-fluoro-benzaldehyde (1.86 g, 15 mmol) in 50 ml of ethanol under argon. The mixture was stored at 0-5° C. overnight and the solid filtered, washed with ethanol and dried. The solid and 3,4-diamino-benzonitrile (2.0 g, 15 mmol) were heated in 7 ml of DMF at 130° C. for 4 hours. After cooling, the mixture was poured into water, the solid filtered and purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 2.49 g (70%) of the desired product. MS (mass spectrum): m/e=238.02 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([O:33][C:34]4[CH:42]=[CH:41][CH:40]=[C:39]5[C:35]=4[CH:36]=[N:37][N:38]5[C:43]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([O:33][C:34]4[CH:42]=[CH:41][CH:40]=[C:39]5[C:35]=4[CH:36]=[N:37][N:38]5[C:43]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[CH:24]=3)[CH2:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of EXAMPLE 521G (2.51 g) in tetrahydrofuran (30 mL) and methanol (10 mL) was added lithium hydroxide (1.0M, 10 mL) and the solution heated to 60° C. After 4 hours the reaction was cooled, diluted with dichloromethane (150 mL) and quenched with 1N aqueous HCl (10 mL) and water (30 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 120 g) eluting with a gradient of 0.25% to 2.5% methanol/dichloromethane over 40 minutes gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:30][CH2:31][CH3:32]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH2:30][CH2:31][CH3:32])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCCBr
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCn1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Temperature: 50 °C
Yield: 65 %

Procedure:
10 Parts of 2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3H-1,2,4-triazol-3-one are dissolved in 300 parts of dimethyl sulfoxide at 100° C. Then there are added 1.6 parts of sodium hydride dispersion 50% and stirring is continued while the mixture is allowed to cool to about 50° C. 3.9 Parts of 1-bromopropane are added and the whole is stirred overnight at room temperature. The reaction mixture is poured onto water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2-propanol. The product is filtered off and dried; yielding 7.5 parts (65%) of 2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-2-propyl-3H-1,2,4 -triazol-3-one.
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=1.CO.[OH-].[Na+].Cl>C1COCC1.O>[C:1]1([CH3:35])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH:2]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3cccc(C)c3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2cccc(C)c2)CCCN3CCCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 7-(2-m-tolyl-3-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1)(69 mg, 0.146 mmol) in THF (1 ml) and water (0.5 ml) at RT was treated with LiOH monohydrate (18.42 mg, 0.439 mmol) and stirred at RT for 4 hours. MeOH (1 ml) and 2M NaOH (1 ml) were added and the mixture was stirred at RT overnight. The resulting mixture was added to water (20 ml) and the pH was adjusted to pH1 with 2M HCl. The aqueous portion was extracted with DCM (×3) and the organic extracts were passed through a phase separating column. The organic solvent was concentrated in vacuo. The crude product was purified by preparative LC-MS (low pH). The appropriate fraction was collected and extracted with DCM (×3), passing the organics through a phase separating column. The solvent was removed in vacuo to afford the title compound;
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the 4-(4-bromo-2-fluorophenoxy)phenol (5.66 g, 0.02 mole) from Step V, methyl 2-bromoproprionate (3.34 g, 0.02 mole) and potassium carbonate (3.06 g, 0.22 mole) in DMSO (30 ml) was stirred, under an atmosphere of nitrogen, at room temperature for 18 hours. The mixture was poured into water (300 ml), and the resulting mixture extracted with ether (2×10 ml). The ether extracts were combined, washed with water (100 ml), dried (MgSO4), and the solvent evaporated to give the desired 2-[4-(4-bromo-2-fluorophenoxy)phenoxy]propionic acid; methyl ester as a yellow oil (6.0 g, 81%); R.I.=1.5628; NMR (CDCl3) was consistent with the assigned structure. The carbon and hydrogen content was as follows:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cc(CO)ccc1NC1CCCCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-cyclohexylamino-3-nitrobenzyl alcohol (21.0 g, 83 mmol) in DCM (300 mL) was added powdered 4A molecular sieves (15 g) and N-methyl morpholine-N-oxide monohydrate (10.8 g, 92.2 mmol). Tetra-n-propylammonium perruthenate (VII) (2.91 g, 8.28 mmol) was then added in a single portion. An initial exotherm was controlled using an ice bath, and then the reaction mixture was stirred at room temperature for 18 hr. The mixture was then reduced to ˜100 mL by evaporation, and loaded onto a column of silica (400 g). The column was eluted with acetone:hexane 1:3 and the spot at 0.30 was collected, affording 4-cyclohexylamino-3-nitrobenzaldehyde as a yellow solid. (11.0 g, 44.3 mmol): 1H NMR (CDCl3, 300 MHz) δ 9.60 (s, 1H), 8.32 (s, 1H), 7.71 (d, J=10 Hz, 1H), 6.73 (d, J=10 Hz, 1H) 3.46-3.32 (m, 1H), 1.90-1.15 (m, 10H).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1>C(O)(=O)C>[CH2:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: Oc1cccc2cnccc12
Solvent: CC(=O)O
Product: Oc1cccc2c1CCNC2
Yield: 90.2 %

Procedure:
Isoquinolin-5-ol (Aldrich, Cat. #H33207)(0.75 g, 5.2 mmol) was dissolved in acetic acid (20.0 mL) in a Parr shaker bottle. The reaction was degassed with nitrogen, and the platinum dioxide (0.050 g) was added. The reaction was charged to 55 Psi hydrogen and shaken. After shaking for 24 h. the reaction was complete. This was filtered to remove the catalyst and concentrated under reduced pressure give a dark amber 1,2,3,4-tetrahydroisoquinolin-5-ol (0.70 g, 90%) as an oil. Analytical LCMS (M+H)+: m/z=150.1.
Reaction SMILES: [O-]CC.[Na+].[Na].FS(O)(=O)=O.[CH2:11]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[NH:17])[CH3:12].C([O:25][CH:26]=[C:27]([C:33](OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C>C(O)C.C(O)(=O)C.O>[O:25]=[C:26]1[NH:18][C:16]([C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH2:11][CH3:12])=[N:17][CH:33]=[C:27]1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1ccccc1C(=N)N
Agent: CC[O-]
Agent: O=S(=O)(O)F
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnc(-c2ccccc2OCC)[nH]c1=O
Yield: 97.3 %

Procedure:
To a solution of sodium ethoxide at 18° prepared from sodium (41 g., 1.78 g-atoms) in ethanol (1 l.), was added a solution of 2-ethoxybenzamidine fluorosulfonate (206.5 g., 0.78 mole) in ethanol (500 ml.). The resulting solution was cooled to 13° and then treated with a solution of diethyl ethoxymethylenemalonate (180 ml., 0.89 mole) in ethanol (400 ml.). The mixture was heated under reflux for 2.25 hours. The mixture was cooled to 10° and then poured into cold water (5 l.) with good stirring. Ice was added as necessary to keep the temperature of the mixture below 20°. the mixture was acidified to pH 5 with glacial acetic acid. The solid material was collected by filtration, washed with water, and dried to give the title compound (218.7 g., 97%). Recrystallization from acetonitrile gave product with m.p. 144°-147°.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][CH:8]([CH3:13])[CH:9]([OH:12])[CH:10]=[CH2:11].[I-].[Na+].C(=O)(O)[O-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:7][CH:8]([CH3:13])[C:9](=[O:12])[CH2:10][CH2:11][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1
Reactant: Brc1ccsc1
Reactant: C=CC(O)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)C(=O)CCc1ccsc1

Procedure:
The title compound was prepared according to General Method 4b using 3-bromothiophene (20 mmol), 4-methyl-1-penten-3-ol (30 mmol), sodium iodide (0.7 mmol), sodium bicarbonate (24 mmol), triphenylphosphine (0.6 mmol), DMF (15 mL), and palladium acetate (0.2 mmol). The title compound was flash chromatographed using EtOAc:hexane (5:95 to 10:90).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:28])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:28]
Reactant: COC(=O)c1nc(-c2ccc(NC(=O)OCc3ccccc3)c(C)c2)oc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(N)c(C)c2)oc1C
Yield: 105.1 %

Procedure:
The same operation as in Example (95b) was performed using methyl 2-(4-{[(benzyloxy)carbonyl]amino}-3-methylphenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (108d) (0.7 g, 1.7 mmol), 10% Pd/C (0.3 g) and methanol (20 mL), to obtain 0.44 g of the title compound as a yellow solid (97%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:18][C:19](=[O:22])[CH2:20]Cl)[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1.[N-:25]=[N+:26]=[N-:27].[Na+]>CC(C)=O>[N:25]([CH2:20][C:19]([NH:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:24])[NH:3][C:2]1=[O:1])[C:9]2=[O:23])=[O:22])=[N+:26]=[N-:27]
Reactant: O=C1CCC(N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)C(=O)N1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 95 %

Procedure:
To a suspension of N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-2-chloroacetamide (1.53 g, 4.4 mmol) in acetone (30 ml) was added sodium azide (0.43 g, 6.6 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo to give 1.49 g (96%) of product as an off-white solid: 1H NMR (DMSO-d6) δ 11.19 (s, 1H), 10.20 (s, 1H), 8.49 (d, J=8.3 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.68 (d, J=7.3 Hz, 1H), 5.17 (dd, J=5.1 and 12.7 Hz, 1H), 4.34 (s, 2H), 2.99-2.84 (m, 1H), 2.65-2.47 (m, 2H), 2.09-2.00 (m, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH2:10]([SH:12])[CH3:11]>ClC1C=CC=CC=1Cl>[CH2:10]([S:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:11]
Reactant: OCc1ccccc1O
Reactant: CCS
Solvent: Clc1ccccc1Cl
Product: CCSCc1ccccc1O
Yield: 87 %

Procedure:
A mixture of 49.6 g (0.4 mol) of 2-hydroxymethyl-phenol, 24.8 g (0.4 mol) of ethylmercaptan and 200 ml of o-dichlorobenzene was heated in a flask equipped with a stirrer and a reflux condenser, under normal pressure, and starting from room temperature, in such a way that there was always a moderate reflux and that the final temperature in the flask did not exceed about 125° C. In total, the mixture was heated under reflux for about 20 hours. Thereafter, working up by distillation gave 2-ethylthiomethyl-phenol in a yield of 87% of theory. The o-dichlorobenzene distilled off could be re-used in a subsequent batch.
Reaction SMILES: [C:1]1([NH:7]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:14]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 230.7 %

Procedure:
830 mg (2.44 mmole) of the aniline compound obtained in step 1 was dissolved in 10 mL of pyridine, 0.340 mL (2.93 mmoles) of benzoylchloride was added, and the mixture was stirred overnight at room temperature. When the reaction had ended, the solvent was removed under reduced pressure. Ethyl acetate and 1N HCl aqueous solution were added to the residue. The mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure, yielding 1.11 g of N-benzoylaniline compound.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:12])[CH2:8][CH2:9]OC.[OH-].[Na+]>>[CH3:13][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:12])[CH:8]=[CH2:9]
Reactant: COCCC(=O)NCCCN(C)C
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NCCCN(C)C

Procedure:
188.3 g (1.0 mole) of N-(3-dimethylaminopropyl)-3-methoxypropionamide (according to Example 13 ) are heated with 1.5 g of sodium hydroxide at 90°-110° C. in a high vacuum. Within about 30 minutes methanol is split off, vigorous forming occurring. The temperature is increased and 103 g (0.66 mole=66% of the theoretical yield) of colorless oil having a Bp0.1 of 96°-100° C. are distilled off.