Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[C@@H:24]([C:25]=2[CH:26]=1)[CH2:23][CH2:22][CH2:21][NH:20]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:20]3[CH2:21][CH2:22][CH2:23][C@@H:24]4[C:25]5[CH:26]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=5[CH2:18][C@H:19]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1ccc2c(c1)[C@H]1CCCN[C@H]1C2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: Cc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Yield: 60 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 60% of theory; LC (method 1): tR=2.75 min; Mass spectrum (ESI+): m/z=332 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1)=[O:4].[CH3:11][O:12][C:13]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:17](=[O:18])[C@@H:16]([NH:15][C:13]([O:12][CH3:11])=[O:14])[CH:20]([CH3:22])[CH3:21])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester in dry DCM (200 mL) was added (S)-2-methoxycarbonylamino-3-methyl-butyric acid (10 g, 55 mmol), HATU (24 g, 63.25 mmol), and triethylamine (16.7 g, 165 mmol. The reaction mixture was stirred at RT overnight. DCM (200 mL) was added and the solution was washed with brine, dried, concentrated and purified by silica gel column chromatography (eluted with petroleum ether:EtOAc 10:1 to 1:4)) to give the title intermediate as a yellow oil (20 g). (m/z): [M+H]+ calcd for C13H22N2O6 303.15. found 303.1.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[C@H:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:8]([OH:10])=[O:9]>C(#N)C>[C:1]([S:3][C@@H:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: CC(C)(C)C[C@@H](Br)C(=O)O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@@H](CC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A slurry of potassium thioacetate (750 mg, 6.58 mmol) and acetonitrile (10 ml, molecular sieves dried) was cooled to 0° C. and treated with a solution of (R)-2-bromo-4,4-dimethylpentanoic acid from part (a) in acetonitrile (2 ml) over 5 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The slurry was filtered. The filtrate was concentrated in vacuo. The residue was diluted in ether (50 ml), washed with two portions of 5% aqueous sodium thiosulfate (50 ml) and brine (25 ml), dried (magnesium sulfate), and concentrated in vacuo. The pale yellow oil was purified by flash chromatography (Merck silica gel, 12×3 cm., 10% methanol/methylene chloride) affording 575 mg of title product as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([O:19][CH3:20])[CH:8]=1.O>CO>[CH:14]1([O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:21])=[O:4])=[CH:8][C:9]=2[O:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)Cc1ccc(OC2CCCC2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(CC(=O)O)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.6 %

Procedure:
Sodium hydroxide (4.75 g, 119 mmol) was added to a solution of (4-cyclopentyloxy-3-methoxy-phenyl)-acetic acid methyl ester (12.4, 46.9 mmol) in methanol) 100 ml)/water (100 ml) and the reaction was stirred at room temperature for 3.5 hours. The methanol was removed under reduced pressure and the aqueous phase was washed with diethylether (100 ml) then acidified to pH 2 using concentrated hydrochloric acid. This was then extracted with ethyl acetate (2×200 ml) and the combined organic extracts were washed with brine (100 ml), dried over Na2SO4 and concentrated under reduced pressure to give (4-cyclopentyloxy-3-methoxy-phenyl)-acetic acid (11.1 g) as a white solid. 1H NMR (400 MHz, CD3OD): δ=6.87 (1H, s), 6.81-6.86 (1H, d), 6.76-6.80 (1H, d), 4.75-4.79 (1H, brs), 3.78 (3H, s), 3.49 (2H, s), 1.71-1.89 (6H, m), 1.56-1.64 (2H, m) ppm. LRMS (electrospray): m/z [M−H]+ 249, [2M−H]+ 499. Anal. Found C, 67.15; H, 7.25. C14H18O4 requires C, 67.18; H, 7.25%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:18]([CH3:20])[CH3:19])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O:25]C(NC(C1CCOC1)C(O)=O)=O)(C)(C)C>>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:10](=[O:17])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:18]1[CH2:19][CH2:21][O:25][CH2:20]1)[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CCOC1
Reactant: CCOC(=O)CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Product: CCOC(=O)CC(=O)C(NC(=O)OC(C)(C)C)C1CCOC1

Procedure:
Procedure same as that for ethyl(S)-4-((tert-butoxycarbonyl)amino)-5-methyl-3-oxohexanoate, using 2-((tert-butoxycarbonyl)amino)-2-(tetrahydrofuran-3-yl)acetic acid as a starting material. 1H NMR (CD3OD, 400 MHz): δ 4.25-4.13 (m, 3H), 4.00-3.45 (m, 4H), 2.75-2.65 (m, 1H), 2.12-1.98 (m, 1H), 1.77-1.62 (m, 1H), 1.49 (s 9H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1Br)=[CH:12][C:11]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([O-])=O.[NH4+].CN(C=O)C>[Pd].O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(C(=O)CC(C)C)cc2c1Br
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)CC(C)C)ccc2[nH]1
Reaction time: 1.17 h

Procedure:
To the mixture of 3-Bromo-5-(3-methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester (408 mg, 1.1 mmol), ammonium formate (10 mg, 1.7 mmol), and 10% Pd/C (200 mg) was added DMF (5 mL) and water (0.625 mL). The mixture was slightly shaked at room temperature for 70 minutes and then filtered through celite. The solvent was evaporated under vacuum to give 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester as light yellow liquid as crude product with the purity of 90%; E1-MS m/z 274.1 (M++H). The crude ethyl ester was dissolved in dioxane (10 mL), Then a solution of LiOH.H2O (195 mg, 4.6 mmol) in water (5 mL) was added to the flask. The mixture was stirred at room temperature for 2 days. Dioxane was stripped under vacuum. 10 mL water was added and extracted with CH2Cl2. Then the aqueous phase was acidified with 6N HCl and extracted with CH2Cl2. The CH2Cl2 phase was then washed with saturated brine and dried over anhydrous Na2SO4. Solvent was removed under vacuum to give 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid (250 mg, 88% for two steps) as white solid. EIMS m/z 246.1 (M++H) (lab-ref: YS-053-141).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][O:5][C:4]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:3]1=2.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:4]3[O:5][CH2:6][C:2]([CH3:19])([CH3:1])[C:3]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)C(C)(C)CO2
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)C(C)(C)CO2
Yield: 48.7 %

Procedure:
Similarly, (2-fluorophenyl)-N-[5-(3,3,6-trimethyl(2,3-dihydrobenzo[b]furan-5-yl))-pyrazin-2-yl]carboxamide (179) (13.8 mg, yield: 48.7%, purity>95%) was prepared from 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (177) (19 mg, 0.075 mmol) and 2-fluorobenzoyl chloride (18 μl).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH2:15])=[C:4]([F:16])[CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([N:15]=[C:24]=[S:25])=[CH:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: Nc1cc(Oc2ncccn2)c(Cl)cc1F
Reactant: S=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1cc(Cl)c(Oc2ncccn2)cc1N=C=S

Procedure:
4-Chloro-2-fluoro-5-(2-pyrimidinyloxy)-benzenamine (50 g) and triethyl amine (42.2 g) were dissolved in anhydrous ethyl acetate (400 ml) and stirred under ice cooling. Thiophosgene (74.3 g) dissolved in ethyl acetate (400 ml) was slowly added to the stirred solution. The mixture was heated at reflux for 2 hr and filtered. Evaporation of the solvent afforded 2-(2-chloro-4-fluoro-5-isothiocyanatophenoxy)-pyrimidine which was used for the next step without purification. 1H NMR, CDCl3, 7.12 (1H, t, J=4.7 Hz), 7.13 (1H, d, J=7.0 Hz), 7.32 (1H, d, J=8.9 Hz), 8.58 (2H, t, J=4.7 Hz).
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>ClCCl>[CH:11]1[C:12]2[S:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][C:10]=1[S:16]([OH:19])(=[O:18])=[O:17]
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2c(c1)Sc1ccccc1S2
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc2c(c1)Sc1ccccc1S2
Reaction time: 4 h

Procedure:
To a stirred solution of thianthrene (6.0 g, 27.7 mmol) in 160 mL of dichloromethane at 0° C. was added dropwise, 2.03 mL (30.5 mmol) of chlorosulfonic acid. The resulting deep purple mixture was stirred for 4 hours and then hexanes were added, and the reaction was filtered to give thianthrene-2-sulfonic acid. This acid (3.18 g, 10.7 mmol) was mixed with 7.36 g (35.3 mmol) of phosphorous pentachloride, and the neat solids were heated to a melt at 110° C. for 2 hours. The resulting mixture was quenched with ice and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated to give the title compound as a green oil which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[S:10][C:9]=2[CH:15]=1)=[O:4].[N-:16]=[N+:17]=[N-:18].[Na+]>C(#N)C>[N:16]([CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[S:10][C:9]=2[CH:15]=1)=[O:4])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)Oc2ccc(C(=O)CCl)cc2S1
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)Oc2ccc(C(=O)CN=[N+]=[N-])cc2S1

Procedure:
A solution of 20 g of 5-chloroacetyl-2,2-dimethyl-1,3-benzoxathiole (VII) in acetonitrile (100 ml) was stirred for two days with 7 g of finely powdered sodium azide. The reaction mixture was filtered, evaporated and the residue recrystallized from methanol to yield 12 g of 5-azidoacetyl-2,2-dimethyl-1,3-benzoxathiole (VIII), m.p. 52°-53° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](OB(C2C=CC=CC=2)O)=[CH:21][CH:20]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)[CH:5]=1
Reactant: Cc1ccc(OB(O)c2ccccc2)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 60.5 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) was converted, using 4-methylphenylphenylboronic acid (120 mg, 0.88 mmol) instead of 4-fluorophenylboronic acid, to the title compound (84 mg, 60%) which was obtained as an off-white solid. MS: m/e=316.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[C:29]1([OH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[O:35]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2ccccc2)cc1)c1ccccc1C(F)(F)F
Yield: 75 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and phenol, the title compound was isolated as a yellow solid in 75% yield (98% purity by HPLC).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11]N)[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3].S(O)(O)(=O)=O.CS[C:35](=[NH:37])[NH2:36]>O>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[N:36]=[C:35]([NH2:37])[N:11]=[C:6]2[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1)[CH2:2][CH3:3]
Reactant: CSC(=N)N
Reactant: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1nc(C)n2nc(N)nc2c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 17.7 %

Procedure:
10 g of 6-n-propyl-2-methyl-4-hydrazino-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine, prepared in Example 12, and 5 g of 2-methyl-2-thiopseudourea sulphate are heated to reflux for 16 hours. After the addition of water, the crystals formed are drained and washed with ether and then with ethyl acetate before taken up in dilute sodium hydroxide solution and extracted with chloroform. The organic phase is dried over magnesium sulphate and evaporated under vacuum, to give a residue which crystallises in a mixture of isopropyl ether and ethyl acetate to give 1.8 g of 7-n-propyl-5-methyl-2-amino-8-[(2 '-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[1,5-c]pyrimidine in the form of crystals of melting point 150° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]#[N:8])=[O:5])[CH3:2].[CH3:9]OS(OC)(=O)=O>>[CH2:1]([O:3][C:4]([N:6]([CH3:9])[C:7]#[N:8])=[O:5])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)NC#N
Product: CCOC(=O)N(C)C#N

Procedure:
Berichte, 62, 1393-1394 (1929) discloses the reaction of the ethoxycarbonylcyanamide with dimethylsulfate to produce N-ethoxycarbonyl-N-methylcyanamide.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH2:7][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)OCc1ccccc1

Procedure:
2.50 g (19.2 mmol) of methyl 3-oxovalerate, 6.23 g (57.6 mmol) of benzyl alcohol and 234 mg (1.92 mmol) of 4-dimethylaminopyridine were heated under reflux in 30 ml of toluene overnight. Ethyl acetate was added to the reaction solution. After washing with 1 N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:6]([O:8]C)=[O:7].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(-c2ccc(C)cn2)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a flask were charged methyl 3-methoxy-5-(5-methylpyridin-2-yl)benzoate (80 mg, 0.2 mmol), barium hydroxide octahydrate (300 mg, 0.95 mmol), and methanol (10 mL). The mixture was stirred at room temperature overnight. 2N HCl (ethyl ether solution, 30 mL) was added and the volatiles were removed under reduced pressure. LC-MS: 244.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])(=[O:20])=[O:19]
Reactant: Cc1ncsc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ncsc1CCOS(C)(=O)=O

Procedure:
The 4-methyl-5-thiazole ethanol (Aldrich, 0.18 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1.[H][H].C(=O)(O)[O-].[Na+]>C(O)C.[C].[Pd]>[CH3:8][C:6]1[CH:7]=[CH:2][N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:5]=1
Reactant: [H][H]
Reactant: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCc1cccc(-c2nccc(C)n2)n1
Yield: 88.9 %

Procedure:
To a solution of 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (2 g) in ethyl alcohol (50 ml), was added 5 % palladium carbon (0.2 g). The mixture was brought into contact with hydrogen gas for two hours. After palladium carbon was filtered off, the reaction solution was concentrated under reduced pressure to give a residue. To the residue, was added saturated aqueous sodium bicarbonate solution (30 ml). The mixture was extracted with chloroform (100 ml) and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to obtain 4-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (1.53 g, yield: 89 %).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]>>[CH2:8]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Oc1ccccc1
Reactant: C=CCCCCCCC
Product: CCCCCCCCCc1ccc(O)cc1
Reaction time: 20 h
Yield: 92 %

Procedure:
A suspension of 190 parts of phenol, 152 parts of propylene trimer and 7 parts of ion exchange resin is prepared in a stirred reactor at 120° C. and 1 bar pressure, the mixture being stirred at 500 rpm. The ion exchange resin is a sulfonated styrene/divinylbenzene copolymer resin, which has been dehydrated under reduced pressure for 20 hours at 100° C. before being used; it has a gel structure and its particle size is from 20 to 150 micrometers. The suspension is then stirred constantly in the reactor at 500 rpm. After 6 hours, 12.1 parts of phenol and 9.8 parts of propylene trimer are introduced per hour at 120° C. and 1 bar pressure and correspondingly 21.9 parts per hour of suspension are filtered through a suction line equipped with a metal filter (pore diameter 10 micrometers) and are subjected to fractional distillation. After 200 hours' operation, 3,145 parts (92% of theory, based on starting material II) of 4-nonylphenol of boiling point 175°-180° C./27 millibars are obtained. The conversion is 57%, based on phenol employed, or 95% based on starting material II.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18]N)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:21].Br[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][CH2:23][C:24]#[N:25])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:21]
Reactant: N#CCBr
Reactant: Cc1ccc2c(c1C)N(CCCN)c1ccccc1S2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1C)N(CCCCC#N)c1ccccc1S2=O
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
2.25 g of 1,2-dimethyl-10-(3-aminopropyl)phenothiazine-5-oxide synthesized in Example 8, 990 mg of bromoacetonitrile and 1.2 g of potassium carbonate were dissolved in 50 ml of N,N-dimethylformamide followed by stirring at 80° C. for 10 min. Then the reaction mixture was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 670 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: C[C@H]1COCCN1Cc1cccc(Br)n1
Product: C[C@H]1COCCN1Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and (3S)-4-[(6-bromopyridin-2-yl)methyl]-3-methylmorpholine (133 mg, 0.49 mmol) as starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCCO
Reactant: Cc1ccc(O)c(NC(=O)OC(C)(C)C)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(OCCCN(C)C)c(NC(=O)OC(C)(C)C)c1
Reaction time: 12 h

Procedure:
To a stirred, cooled (about 0° C.) solution of (2-hydroxy-5-methyl-phenyl)-carbamic acid tert-butyl ester (447 mg, 2.0 mmol), triphenyl phosphine (525 mg, 2.0 mmol), and 3-(dimethylamino)-1-propanol (237 μL, 2.0 mmol) in dry tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (394 μL, 2.0 mmol) in 1 mL of tetrahydrofuran). After stirring for 12 hours, the reaction was diluted with 30 mL of ethyl acetate and washed with 30 mL of 10% aqueous sodium carbonate (2×30 mL), brine (1×30 mL), then dried (MgSO4) and filtered. The filtered solution was concentrated under reduced pressure to provide the desired crude product.
Reaction SMILES: [OH:1][CH:2]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=O.C[O-].[Na+].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].Cl>CO>[CH2:26]([NH:30][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([OH:1])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCC(O)CCCCCCCCCCC(=O)NCCCC

Procedure:
50 g of methyl 12-hydroxystearate, 300 ml of methanol and 20 ml of a 28% methanol solution of sodium methoxide were mixed, and 50 ml of n-butylamine was added thereto. The resulting mixture was heat-refluxed for 6.5 hours. After cooling, the reaction mixture was poured into dilute hydrochloric acid, and the precipitated crystals were filtered to obtain 47 g of N-butyl-12-hydroxystearic acid amide having a melting point of 100°-102° C.