Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[N:42]=[C:41]([S:52][CH2:53][C:54]3[N:55]=[C:56]([C:59]4[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=4)[S:57][CH:58]=3)[C:40]=2[C:66]#[N:67])=[CH:35][CH:34]=1)=[O:28])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:68]>ClCCl.C(OCC)C>[ClH:65].[ClH:68].[NH2:8][C@H:9]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([N:47]3[CH2:48][CH2:49][CH2:50][CH2:51]3)[N:42]=[C:41]([S:52][CH2:53][C:54]3[N:55]=[C:56]([C:59]4[CH:60]=[CH:61][C:62]([Cl:65])=[CH:63][CH:64]=4)[S:57][CH:58]=3)[C:40]=2[C:66]#[N:67])=[CH:37][CH:38]=1)=[O:28])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCC(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCCC2)c(C#N)c1-c1ccc(OCCOC(=O)CCNC(=O)[C@@H](N)CCCCN)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
950 mg (0.976 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N2,N6-bis(tert-butoxycarbonyl)-L-lysyl-beta-alaninate (Example 24A) were initially charged in 25 ml of dichloromethane. 9.76 ml of a 1N solution of hydrogen chloride in diethyl ether were added, and the reaction solution was then stirred at RT overnight. For 15 min, argon was introduced into the reaction mixture, and the mixture was then concentrated by evaporation. This gave 816 mg (99% of theory) of the target compound.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([Br:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.[OH-].[Na+].Cl>CO.CCOC(C)=O>[Br:11][C:7]1[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:15])=[O:2])=[CH:5][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cc(C)c(Br)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1Br
Reaction time: 12 h
Yield: 47 %

Procedure:
4-Bromo-5-methyl-3-nitrobenzoic acid methyl ester ((Example 294: step a (11.6 g, 42.3 mmol) was dissolved in MeOH (400 mL) at rt and 2N NaOH (43 mL) was added dropwise over 30 min via addition funnel. The solution was stirred for 12 hr during which, precipitate appeared, and sm disappeared (TLC shows only baseline spot in 30% EtOAc). The pH was adjusted to ˜2 with conc HCl and the methanol was removed in vacuo. EtOAc (300 mL) was added to the aqueous slurry and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL) and then discarded. TLC analysis of the combined organic extracts showed two products (40% EtOAc in Hexanes, 4% AcOH). The combined organic extracts were washed with a 3:1 solution of 0.5N NaH2PO4/0.5N NaOAc (˜30×50 mL portions) until removal of the o-nitrobenzoic acid (lower spot on TLC, 40% EtOAc in Hex, 4% AcOH) was complete. The organic layer was then washed with brine and dried over sodium sulfate. Concentration of the solution yielded 5.4 g (47%) of a white solid. 1H NMR (CD3OD) δ 8.10 (m, 2H), 2.54 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13](OC(=O)C)[C:14]([N:16]([CH3:30])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[O:26][CH:27]([CH3:29])[CH3:28])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O>ClCCl>[CH3:30][N:16]1[C:14](=[O:15])[CH:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[C:23]2[C:18](=[C:19]([O:26][CH:27]([CH3:29])[CH3:28])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH2:17]1
Reactant: COc1cccc(CN(C)C(=O)C(OC(C)=O)c2cc(OC)c(OC)c(OC)c2)c1OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2C(=O)N(C)Cc3c2ccc(OC)c3OC(C)C)cc(OC)c1OC

Procedure:
A solution of the amide from step 2 above (6.2 g) in dichloromethane (60 ml) and trifluoroacetic acid (20 ml) was refluxed for 6 hours. The reaction mixture was concentrated to dryness and the residue was crystallized from methanol, giving 2-methyl-4-(3,4,5-trimethoxyphenyl)-8-isopropoxy-7-methoxy-1,4-dihydro-3(2H)-isoquinolinone (4.8 g), m.p. 128-129° C.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH3:25][NH:26][CH2:27][C:28]#[CH:29]>O1CCCC1>[CH3:25][N:26]([CH2:27][C:28]#[CH:29])[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3]
Reactant: C#CCNC
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCN(C)C(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
A mixture of 5.6 g (0.02 mole) of 1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine and 3 g (0.022 mole) of potassium carbonate in 50 ml of tetrahydrofuran was treated while stirring with 1.52 g of N-methylpropargylamine. After stirring for 15 min, 10 g of ice was added and stirring continued for an additional 72 hr. The tetrahydrofuran was decanted from the salt paste and concentrated on a rotary evaporator to yield an amber oil, 5.9 g. This oil solidified when cooled to -70° C. and was recrystallized from hexane to yield 4.6 g (74.2%) of fine white crystals, m.p. 71°-73° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]([C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@@H:24]([C@H:32]([C@@H:34]1[C@@H:38]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C@@H:37]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@H:36]([N:55]2[CH:60]=[CH:59][C:58](=[O:61])[N:57]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:56]2=[O:71])[O:35]1)[OH:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[Si:40]([O:39][C@H:38]1[C@@H:37]([O:47][Si:48]([C:51]([CH3:53])([CH3:54])[CH3:52])([CH3:49])[CH3:50])[C@H:36]([N:55]2[CH:60]=[CH:59][C:58](=[O:61])[N:57]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:56]2=[O:71])[O:35][CH:34]1[C@H:32]([OH:33])[C@@H:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:23][CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:21])[C@H:11]([C@@H:12]([OH:14])[CH3:13])[NH:10][C:9](=[O:22])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:42])[CH3:41]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 53.8 %

Procedure:
By using an analogous procedure to that described for Example 1, a solution of [(1S,2S)-2-hydroxy-1-(3-oxo-propylcarbamoyl)-propyl]-carbamic acid benzyl ester (108 mg, 0.35 mmol, obtained from Reference Example 18), tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (230 mg, 0.319 mmol, obtained from Reference Example 6), acetic acid (3 drops), and sodium triacetoxyborohydride (135 mg, 0.64 mmol) in anhydrous tetrahydrofuran (5 ml) was stirred under nitrogen at room temperature for 4 hours. The residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (174 mg, 54%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15]O)[C:10]=1[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][Cl:20])[C:10]=1[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCOc1ccnc(CO)c1C
Solvent: ClC(Cl)Cl
Product: CCCCCCCOc1ccnc(CCl)c1C
Yield: 180.7 %

Procedure:
14.5 g (0.061 mol, 1.0 eq.) of 4-heptyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 700 mL of chloroform, and 37.0 g (0.311 mol, 5.1 eq.) of thionyl chloride was added dropwise at 22 to 30° C. Subsequently, the mixture was heated to reflux for 30 minutes and then concentrated, to obtain 28.2 g of 4-heptyloxy-2-chloromethyl-3-methylpyridine as a black oily matter.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([C:17](=[O:19])[CH3:18])[CH:9]=[CH:8]2.CO>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([C:17](=[O:19])[CH2:18][Br:1])[CH:9]=[CH:8]2
Reactant: BrBr
Reactant: COc1cc2ccc(C(C)=O)cc2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ccc(C(=O)CBr)cc2cc1OC
Yield: 66.9 %

Procedure:
A solution of bromine (4.5 g, 0.029 mol) in chloroform (30 ml) is added dropwise to a solution of 6,7-dimethoxy-2-acetylnaphthalene (6.7 g, 0.029 mol) in a mixture chloroform (70 ml)/methanol (15 ml). Once the reaction mixture discoloures, it is concentrated to dryness and the residue is treated with a mixture ethyl ether/isopropyl ether. The thus obtained solid is triturated with methanol yielding 6,7-dimethoxy-2-(2-bromoacetyl)naphthalene (6 g). M.p. 120°-122° C.
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[N:6][C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[H-].[Na+].C(Br)C=C.[O:27]1C[CH2:30][CH2:29][CH2:28]1>>[CH2:19]([O:18][C:16]([C:7]1[NH:6][C:5]2=[CH:4][C:3]([O:27][CH2:28][CH:29]=[CH2:30])=[N:2][C:10]2=[CH:9][C:8]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cc2c(ccn2O)nc1C(=O)OCC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Product: C=CCOc1cc2[nH]c(C(=O)OCC)c(C(=O)OCC)cc-2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Diethyl 1-hydroxypyrrolo[3,2-b]pyridine-5,6-dicarboxylate (6.2 g, 0.022 mol)is dissolved in (200 mL) dry tetrahydrofuran and cooled to 0° C. under nitrogen. Sodium hydride (0.77 g, 0.033 mol) is added in portions over ten minutes and the reaction is stirred for 30 minutes at 0° C. Allyl bromide (2.01 mL, 0.024 mol) is added all at once to the suspension and the mixture allowed to warm to room temperature and then stirred for 16 hours. The mixture is filtered and the filtrate concentrated in vacuo. The resulting oil is chromatographed using 4:1 hexanes/ethyl acetate and then increasing the polarity to 2:1 hexanes/ethyl acetate to give the product as a yellow oil in 89% yield.
Reaction SMILES: [C:1](=[C:4]1[NH:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[H-].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH3:16]>CN(C)C=O>[CH2:13]([N:6]1[C:5](=[O:10])[C:4](=[C:1]([CH3:3])[CH3:2])[NH:8][C:7]1=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: CC(C)=C1NC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)NC(=C(C)C)C1=O
Temperature: 50 °C
Yield: 84.1 %

Procedure:
5-Isopropylidenehydantoin (5.6 g 0.04 mole) Journal of the Chemical Society, 2265 (1955) was added to a stirred suspension of sodium hydride (2.0 g 50% dispersion-oil removed by washing with light petroleum) in dry dimethylformamide (50 ml) and the mixture then heated at 50° C. for 15 minutes after which time a cream coloured solid separated. The mixture was cooled to room-temperature, a solution of n-butyl bromide (6.0 g 0.044 mole) in dry dimethylformamide (25 ml) added and the mixture heated at 80° C. for 4 hours. The mixture was cooled to room temperature and evaporated to dryness in a rotary evaporator under reduced pressure. The residue was dissolved in water (200 ml) and extracted with ether (3×50 ml). The ethereal solution was dried (MgSO4) and the solvent removed to yield a solid (6.6 g) which was crystallised from light petroleum (b.p. 60°-80° C.) to yield the title compound as needles, m.p. 130° C. Yield=4.3 g=55%.
Reaction SMILES: [N-]=[N+:2]=[N-:3].[Na+].CCCC(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.ClC1C=CC(C([CH:33]2[CH2:37][CH:36]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=3)[N:35]([C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:47][CH:46]=3)[C:34]2=[O:56])=O)=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C(#N)C.C(OCC)(=O)C>[N+:2](=[C:33]1[CH2:37][C@H:36]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[N:35]([C:45]2[CH:46]=[CH:47][C:48]([O:51][C:52]([F:55])([F:53])[F:54])=[CH:49][CH:50]=2)[C:34]1=[O:56])=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(Cl)cc1)C1CC(c2cccc(F)c2)N(c2ccc(OC(F)(F)F)cc2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCC(C)C
Product: [N-]=[N+]=C1C[C@H](c2cccc(F)c2)N(c2ccc(OC(F)(F)F)cc2)C1=O
Yield: 70.2 %

Procedure:
Dissolve sodium azide (2.6 g, 40 mmol) and tetrabutylammonium bromide (260 mg, 0.8 mmol) in 2N sodium hydroxide solution (50 mL), add isohexane (50 mL) and stir while cooling in an ice-water bath. Add trifluoromethanesulfonic anhydride (2.0 mL, approx 12 mmol) dropwise, stir for 10 minutes with cooling. Dissolve (5R)-(3-(4-chlorobenzoyl-5-(3-fluoro-phenyl)-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-2-one (1.1 g, 2.3 mmol) in acetonitrile (30 mL), add to the reaction mixture and stir vigorously for 30 minutes. Dilute the reaction mixture with ethyl acetate (150 mL) and wash with brine. Collect the organic phase, dry over anhydrous magnesium sulfate, evaporate and purify on a silica gel column (isohexane-ethyl acetate) to give the titled compound (590 mg, 70% yield) MS (m/z): 366 (M+1).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH3:29][N:24]1[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH3:28])=[N:25]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(C)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid. MS (ESI): m/z=418.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:2]1[O:4][CH2:3]1.[CH3:12][C:13]([NH2:24])([CH3:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][NH:24][C:13]([CH3:23])([CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: CCCCCCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 28.1 %

Procedure:
Using the method of Example 5, supra, 1-hexyl glycidyl ether (175 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 95 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 216 (M−121), 163 (11), 121 (22), 114 (14); 1H-NMR (CDCl3) δ 7.05 (2H, d, J=8.7), 6.79 (2H, d, J=8.7), 3.77 (1H, m), 3.75 (3H, s), 3.41 (4H, m), 2.97 (2H, broad), 2.79 (1H, dd, J=11.7 and 4.1), 2.64 (3H, m), 1.52 (2H, m), 1.26 (6H, m), 1.04 (3H, s), 1.03 (3H, s), 0.85 (3H, t, J=6.7); 13C-NMR (CDCl3) δ 158.1, 131.3, 129.9, 113.4, 73.4, 71.7, 68.9, 55.1, 53.6, 46.3, 44.6, 31.6, 29.5, 26.5, 26.4, 25.7, 22.6, 14.0; FT-IR, cm−1 3405 (broad), 1611, 1512, 1245, 1116, 824.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][C:23](=[O:37])[CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH:11]=[CH:12][C:13]=1[O:14]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(N(CC)CC)C>[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][C:23](=[O:37])[CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(CCCC(=O)C=Cc2ccc(OC3CCCCO3)c(OC3CCCCO3)c2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(CCCC(=O)C=Cc2ccc(O)c(O)c2)cc1OC
Reaction time: 1 h
Yield: 82 %

Procedure:
In 5 ml of absolute methanol was dissolved 100 mg of 1-(3,4-bistetrahydropyranyloxyphenyl)-6-(3,4-dimethoxyphenyl)-3-oxo-1-hexene obtained in Example 15-(1). A catalytic amount of p-toluenesulfonic acid was added to the solution at 0° C. and a stirring was effected at the same temperature for 1 hour. After the reaction, 1 drop of triethylamine was added to the reaction mixture and then the mixture was concentrated to give crude product. By purification of the crude product by means of column chromatography (silica gel/hexane:ethyl acetate=1:1), 55 mg of the above caption compound was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:23]2[C:22](=[O:24])[CH2:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)([CH3:4])([CH3:3])[CH3:2]>[Pd].C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:23]2[C:22]([OH:24])=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1-n1c2c(c3ccccc31)C=CCC2=O
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)c1ccccc1-n1c2ccccc2c2cccc(O)c21
Yield: 84.6 %

Procedure:
In a 500 ml two-neck flask, N-(t-butylphenyl) carbazolone (Compound F, 13 g) and diphenylether (100 ml) were mixed, and the 10% Pd/C (13 g) was added thereto. This reaction solution was refluxed and stirred for 30 minutes to 1 hour. When the reaction was completed, 80% of diphenylether was removed by distillation under reduced pressure, and a catalyst was removed using celite. The filtrate was washed again with ethylacetate. The filtrate was concentrated under reduced pressure and separated using a column chromatography, thereby obtaining 11 g of N-(t-butylphenyl)hydroxycarbazole (Compound G).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[CH:9]2)([O-])=O.O.[NH2:19]N>C(O)C.[Pd]>[NH2:1][C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:14][CH3:15])=[C:7]([O:16][CH3:17])[CH:6]=2)[CH:11]=[CH:12][C:13]=1[NH2:19]
Reactant: NN
Reactant: COc1cc2cccc([N+](=O)[O-])c2cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COc1cc2ccc(N)c(N)c2cc1OC

Procedure:
5-Nitro-2,3-dimethoxynaphthalene (0.483 mmol) was dissolved in 4.0 ml of ethanol. The resulting solution was admixed with 0.18 ml of hydrazine hydrate and 18.5 mg of 10% palladium/carbon catalyst, and heated under reflux for 80 minutes. After cooling, the palladium/carbon catalyst was filtered off, and the filtrate was concentrated. The crude material thus formed was not purified further and was used as such for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][N:21]=1)[C:16]([OH:18])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[N+:25]([O-:52])[CH:26]=[C:27]([Cl:51])[C:28]=1[CH2:29][C@@H:30]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)[O:31][C:32](=[O:35])[CH2:33]O>>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][N:21]=1)[C:16]([O:18][CH2:33][C:32]([O:31][C@H:30]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)[CH2:29][C:28]1[C:27]([Cl:51])=[CH:26][N+:25]([O-:52])=[CH:24][C:23]=1[Cl:22])=[O:35])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N(c1cc(C(=O)O)ccn1)S(C)(=O)=O
Product: CC(C)(C)OC(=O)N(c1cc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)ccn1)S(C)(=O)=O

Procedure:
This Step was performed as Step 10, Scheme 21, starting with 2-(N-(tert-butoxycarbonyl)methylsulfonamido)isonicotinic acid and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (See Scheme 21, step 6-9)
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][NH:11][CH2:10][NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][NH:11][CH2:10][NH:9][C:8]2=[S:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1NCNCC1(c1ccccc1)c1ccccn1
Product: S=C1NCNCC1(c1ccccc1)c1ccccn1

Procedure:
Treatment of 1,2,3,6-tetrahydro-5-phenyl-5-(2-pyridyl)-4(5H)-pyrimidinone with phosphorus pentasulfide as described in the procedure of Example 1 gives 1,2,3,6-tetrahydro-5-phenyl-5(2-pyridyl)-4(5H)-pyrimidinethione.
Reaction SMILES: C(O[C:4](=[N:14][CH3:15])[CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13])C.[C:16]([NH2:22])(=[O:21])[C:17]([NH:19][NH2:20])=O>CN(C)C=O>[F:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([F:13])[C:6]=1[CH2:5][C:4]1[N:14]([CH3:15])[C:17]([C:16]([NH2:22])=[O:21])=[N:19][N:20]=1
Reactant: CCOC(Cc1c(F)cccc1F)=NC
Reactant: NNC(=O)C(N)=O
Solvent: CN(C)C=O
Product: Cn1c(Cc2c(F)cccc2F)nnc1C(N)=O

Procedure:
The reaction of 320 mg (1.5 mmol) of 1-ethoxy-2-(2,6-difluorophenyl)-1-(N-methylimino)-ethane and 155 mg (1.5 mmol) of oxalic acid monoamide monohydrazide can be carried out, in a manner analogous to that described in Example 1, but using 5 ml of N,N-dimethylformamide as solvent. 102 mg (27% of the theoretical yield) of 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide of m.p. 186-189° are likewise obtained.
Reaction SMILES: C1C=CC=CC=1.[C:7]([NH2:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH3:8].C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25]>C(OCC)C.C1(C)C=CC=CC=1>[N:16]([C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH3:8])=[C:24]=[O:25]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(N)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)(N=C=O)c1ccccc1
Temperature: 60 °C

Procedure:
To a benzene (2 mL) solution of cumylamine (1.80 g, 13.3 mmol) and triethylamine (1.86 mL, 13.3 mmol) was added a 20% toluene solution of phosgene (17.5 mL, 33.3 mmol) dropwise. After completion, the reaction mixture was heated to 60° C. for 2 hours. It was then cooled to room temperature, charged with diethyl ether (20 mL), and filtered. Concentration of the filtrate in vacuo afforded the title compound. This crude product was used in the subsequent step without further purification.