Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]([C:43]3[C:51]4[C:46](=[CH:47][C:48]([C:52]#[N:53])=[CH:49][CH:50]=4)[N:45]([CH3:54])[CH:44]=3)[C:28]([NH:30][S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=3)(=[O:33])=[O:32])=[O:29])=[CH:26][C:21]=2[O:20][CH2:19]1>C1(C)C=CC=CC=1>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]([C:43]3[C:51]4[C:46](=[CH:47][C:48]([C:52]5[N:5]=[N:6][NH:7][N:53]=5)=[CH:49][CH:50]=4)[N:45]([CH3:54])[CH:44]=3)[C:28]([NH:30][S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=3)(=[O:32])=[O:33])=[O:29])=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C#N)ccc23)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(-c4nn[nH]n4)ccc23)cc1

Procedure:
Trimethylsilylazide (0.23 ml, 1.74 mmol) and dibutyl tin oxide (52 mg, 0.2 mmol) were added to a solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-cyano-1-methyl-1H-indole (the product of Example 51, 300 mg, 0.58 mmol) in toluene (10 ml) and the solution was heated at reflux under an atmosphere of nitrogen for 14 h. The analysis showed incomplete reaction. Further aliquots of trimethylsilylazide (0.23 ml, 1.74 mmol) and dibutyl tin oxide (52 mg, 0.2 mmol) were added and heating was continued at reflux for a further 24 h. The reaction was cooled and concentrated. The crude product was purified by flash column chromatography (gradient elution from 95% dichloromethane/5% methanol to 90% dichloromethane/10% methanol) giving a pale pink solid (100 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)=[CH:8][CH:7]=1>CCO>[CH3:1][N:2]([CH3:4])[N:3]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([Br:5])=[CH:11][CH:10]=1
Reactant: CN(C)N
Reactant: O=C1CCCCC1Cc1ccc(Br)cc1
Solvent: CCO
Product: CN(C)N=C1CCCCC1Cc1ccc(Br)cc1

Procedure:
Anhydrous N,N-dimethylhydrazine (17 ml) (3,7 eq.) was quickly poured in a solution of 2-[(4-bromophenyl)methyl]-cyclohexanone (16 g) (0.06 mol) in EtOH (200 ml). The reaction mixture was refluxed for 10 h, then concentrated to dryness. The residue was partitioned between tBuOMe and water, the organic phase washed twice with water, dried over magnesium sulfate and concentrated to yield 2-[(4-bromophenyl)methyl]-cyclohexanone dimethylhydrazone (16 g) as a yellow oil. 1H NMR (CDCl3): 7.35 (2H, d), 7.05 (2H, d), 3.05 (1H, dd), 2.4 (6H,s), 2.7-2.2 (4H, m), 1.8-1.3 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.[F:14][CH:15]([F:24])[CH2:16][N:17]1[CH:21]=[C:20](I)[N:19]=[C:18]1[CH3:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:20]2[N:19]=[C:18]([CH3:23])[N:17]([CH2:16][CH:15]([F:24])[F:14])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(I)cn1CC(F)F
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1CC(F)F

Procedure:
The title compound, MS: m/e=282.0 (M+H+), was prepared in accordance with the general method of example A, step 2, from 2-chloro-4-trimethylsilanylethynyl-pyridine and 1-(2,2-difluoro-ethyl)-4-iodo-2-methyl-1H-imidazole.
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCl>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Reactant: NCCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C[C@H]1C(=O)N(CCCCO)CCN1C(=O)OCc1ccccc1
Yield: 65.5 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (24.3 g, 80 mmol) in dichloromethane (130 mL) was added at room temperature over 15 min to a suspension of 4-amino-1-butanol (7.12 g, 80 mmol), acetic acid (9.6 g, 0.16 mol), and sodium triacetoxyborohydride (25.4 g, 0.12 mol), then after 16 h triethylamine (16.2 g, 0.16 mol) was added, and the reaction mixture was concentrated under vacuum. The residue was partitioned between 2 M aq. sodium carbonate solution and ethyl acetate. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloromethane, then dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) afforded the title compound (16.8 g, 66%). Yellow oil, MS (ISP)=321.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)C.[H][H]>[Pd].CO>[F:13][C:11]1[CH:12]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:14][C:4](=[O:3])[CH2:5][NH:6]2
Reactant: [H][H]
Reactant: CCOC(=O)CNc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=C1CNc2cc(F)ccc2N1

Procedure:
A mixture of N-(5-fluoro-2-nitrophenyl)glycine ethyl ester (XI, EXAMPLE 5, 28.60 g), palladium on carbon (10%, 1.01 g) and methanol (500 ml) is shaken under 45 psi of hydrogen on a Parr shaker. After 2 hr an additional 0.54 g of 10% palladium on carbon catalyst is added. The mixture is shaken for an hour at 42 psi and then the catalyst is removed by filtration. p-Toluenesulfonic acid (0.314 g) is added to the filtrate. The solution is concentrated under reduced pressure to a volume of about 250 ml and then stirred at 20°-25°. The reaction is then further concentrated and dichloromethane is added. The solid that formed is collected and chromatographed on 800 ml of silica gel (column) eluting with dichloromethane/methanol (98/2). The appropriate fractions are pooled and concentrated and triturated with a small amount of dichloromethane. The solid is collected, dried, and triturated a second time with dichloromethane and redried to give the title compound, mp 176.0°-177.5°; NMR (CDCl3) 3.95, 3.99, 6.42, 6.63 and 8.33 δ.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][OH:12].Cl[C@H:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCc1cc(O)ccc1F
Reactant: COC(=O)[C@@H](C)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)[C@H](C)Oc1ccc(F)c(CCCO)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a mixture of 4-fluoro-3-(3-hydroxypropyl)phenol (1.5 g), methyl (2R)-2-chloropropanoate (1.30 g) in DMSO (7.5 mL) was added Cs2CO3 (3.45 g) at ambient temperature. The mixture was stirred at 60° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed successively with water (30 mL) two times and brine (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was purified by silica gel column chromatography (n-hexane:EtOAc=4:1-2:1) to give methyl(2S)-2-[4-fluoro-3-(3-hydroxypropyl)phenoxy]propanoate (1.51 g) as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH2:12][C:11]2[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]4[N:33]=[C:32]5[C:27]([CH:28]=[CH:29][C:30](=[O:34])[NH:31]5)=[CH:26][CH:25]=4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH:4]=1.Cl>C(O)C.O1CCCC1>[O:2]=[C:3]1[CH2:12][C:11]2[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]4[N:33]=[C:32]5[C:27]([CH:28]=[CH:29][C:30](=[O:34])[NH:31]5)=[CH:26][CH:25]=4)[CH2:17][CH2:18]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: COC1=CCc2cccc(N3CCN(CCCCOc4ccc5ccc(=O)[nH]c5n4)CC3)c2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CCc2cccc(N3CCN(CCCCOc4ccc5ccc(=O)[nH]c5n4)CC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.5 %

Procedure:
7-{4-[4-(7-Methoxy-5,8-dihydro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-1H-[1,8]naphthyridin-2-one (360 mg, 0.78 mmol) was dissolved in a mixture of ethanol (6 mL) and tetrahydrofuran (2 mL). To this was added 10% hydrochloric acid (1.5 mL) and the mixture was stirred at room temperature for 15 minutes, then quenched with saturated sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (20 mL) and the organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The crude solid was purified by column chromatography (6:94 triethylamine/ethyl acetate) to yield the title compound (263 mg, 75%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 7.76 (d, 1H), 7.60 (d, 1H), 7.20 (t, 1H), 7.00–6.95 (m, 2H), 6.60 (d, 1H), 6.50 (d, 1H), 4.40 (t, 2H), 3.60 (s, 2H), 3.04 (t, 2H), 2.90–2.80 (m, 4H), 2.80–2.40 (m, 8H), 1.90–1.60 (m, 4H), MS ES+ 447.05 (M+H)+ (Exact mass: 446.23).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][N:11]([CH2:19][C:20]([NH2:22])=[O:21])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([N:25]([CH2:34][CH3:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]N)[CH3:24].CC1C=C(C2C=NN(CC(OCC)=O)C=2C2C=CC=CC=2)C=CC=1.CC1C=C(CC(C2C=CC=CC=2)=O)C=CC=1>>[CH2:34]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:22][C:20](=[O:21])[CH2:19][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH:9]=[N:10]1)[CH3:35]
Reactant: CCN(CC)CCCCCCCN
Reactant: Cc1cccc(-c2cnn(CC(N)=O)c2-c2ccccc2)c1
Agent: CCOC(=O)Cn1ncc(-c2cccc(C)c2)c1-c1ccccc1
Agent: Cc1cccc(CC(=O)c2ccccc2)c1
Product: CCN(CC)CCCCCCCNC(=O)Cn1ncc(-c2cccc(C)c2)c1-c1ccccc1

Procedure:
By a process substantially similar to that of Example 30 it is contemplated that N-7-(diethylamino)heptyl]-4-(3-methylphenyl)-5-phenyl-1H-pyrazole-1-acetamide may be synthesized from N,N-diethyl-1,7-heptanediamine and ethyl 4-(3-methylphenyl)-5-phenyl-1H-pyrazole-1-acetate, which is synthesized by a process substantially similar to that of Example 1B from 2-(3-methylphenyl)-1-phenylethanone.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[C:4](#[N:7])[CH:5]=[CH2:6].[OH-].[Na+]>>[CH:1]([CH:2]([CH2:6][CH2:5][C:4]#[N:7])[CH2:6][CH2:5][C:4]#[N:7])=[O:3]
Reactant: CC=O
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Product: N#CCCC(C=O)CCC#N
Yield: 40 %

Procedure:
In the presence of alkaline catalysts, acrylonitrile reacts with aldehydes, the α-carbon atoms of which possess one or two hydrogen atoms, forming 3-substituted propionitriles (U.S. Pat. No. 2,353,687). This so-called "cyanoethylation" reaction also occurs with other compounds which have an active hydrogen atom. For example, 2-ethyl butyraldehyde and acrylonitrile react in the presence of catalytic amounts of 50 percent caustic potash solution forming 2-(β-cyanoethyl)-2-ethyl butyraldehyde. A yield of 76.6 percent results after a reaction period of 4.5 hours. (H. A. Bruson, Th. W. Riener, J. Am. Chem. Soc., 66, 57 [1944]). The reaction is strongly exothermal. Acetaldehyde reacts with acrylonitrile in the presence of a 50 percent caustic soda solution forming γ-formylpimelonitrile. For a yield of 40-50%, the reaction period amounts to 2-3 hours. Under the same conditions, propionaldehyde forms 4.9 percent 2-methyl-4-cyanobutyraldehyde (U.S. Pat. No. 2,409,086). 2,2-dimethyl-4-cyano-butyraldehyde is formed in up to 60 percent yield from the reaction between isobutyraldehyde and acrylonitrile.
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]2[CH2:4][CH2:3][CH2:2][C:1]2=[O:6])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCCO1
Reactant: Nc1cccc2cccnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCCN1c1cccc2cccnc12
Reaction time: 2 h

Procedure:
A mixture of γ-butyrolactone (9.5 g), technical grade 8-aminoquinoline (14.4 g), p-toluenesulphonic acid monohydrate (1.90 g) and mixed xylenes (15 ml) were refluxed with a Dean Stark trap prefilled with xylenes. After one hour γ-butyrolactone (9.0 g) was added and reflux was resumed for two hours. The residue obtained by concentration by vacuum distillation (≃15 mm Hg) of the reaction mixture was extracted with hot ethyl acetate (100 ml). The solid which formed upon cooling the ethyl acetate solution was recrystallized from acetone giving 1-(8-quinolyl)-2-pyrrolidinone, (m.p. 119°-123°), identical by tlc with the product of Example 1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[N:4]=[CH:3]1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[C:21]([O:27][CH2:28][CH2:29][O:30][C:31]4[N:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=4)=[N:22][N:23]([CH3:26])[C:24]=3[NH2:25])=[CH:19][C:14]=2[O:13][CH2:12]1.CN(C1C=CC=CN=1)C.N1C=C(S(N)(=O)=O)N=C1>N1C=CC=CC=1>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[C:21]([O:27][CH2:28][CH2:29][O:30][C:31]4[N:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=4)=[N:22][N:23]([CH3:26])[C:24]=3[NH:25][S:7]([C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)(=[O:9])=[O:8])=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccccn1
Agent: NS(=O)(=O)c1c[nH]cn1
Solvent: c1ccncc1
Product: Cn1cnc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)c1
Reaction time: 48 h

Procedure:
1-Methyl-1H-imidazole-4-sulfonyl chloride (45 mg) was carefully added at room temperature under an atmosphere of nitrogen to a solution of 4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-ylamine (Preparation 48) (50 mg) and dimethylaminopyridine (16 mg) in anhydrous pyridine (2.4 ml). The reaction was stirred for two days, then the mixture was concentrated under reduced pressure and a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml) and brine (6 ml) were sequentially added. The aqueous phase was extracted with ethyl acetate (2×8 ml) and the combined organic phases were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The black residue was purified by preparative TLC (silica) eluted with dichloromethane:methanol (95:5) yielding a mixture of title compound and N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-1-methyl-N-[(1-methyl-1H-imidazol-4-yl)sulfonyl)]-1H-imidazole-4-sulfonamide. The title compound was purified by HPLC (5.4 mg).
Reaction SMILES: [CH:1]([C:3]1[S:7][S:6][C:5](=[S:8])[C:4]=1[CH3:9])=[O:2].[CH3:10][I:11]>>[I-:11].[CH:1]([C:3]1[S:7][S:6][C+:5]([S:8][CH3:10])[C:4]=1[CH3:9])=[O:2]
Reactant: Cc1c(C=O)ssc1=S
Reactant: CI
Product: CS[c+]1ssc(C=O)c1C
Product: [I-]

Procedure:
5-Formyl-4-methyl-1,2-dithiole-3-thione is dissolved in an excess of methyl iodide.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:11]1)=[O:7])(C)(C)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35](C(O)=O)=[C:34]([O:42][CH3:43])[CH:33]=1>>[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35]([C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])[CH2:11]2)=[O:7])=[C:34]([O:42][CH3:43])[CH:33]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(CCCCCCN)C1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@@H]1CCN(CCCCCCNC(=O)Nc2ccccc2)C1

Procedure:
6-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)hexylamine (1.00 g) as starting compound was reacted and treated in the same manner as in Example 34 using phenyl isocyanate (0.38 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.67 g) to give 4-amino-5-chloro-2-methoxy-N-((3S)-1-(6-(3-phenylureido)hexyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[CH3:13][O:14][CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].[Br:21]C(CBr)=C>C1COCC1>[Br:21][C:5](=[CH2:6])[CH2:7][C:15]([O:14][CH3:13])([CH3:20])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)OC
Reactant: C=C(Br)CBr
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(Br)CC(C)(OC)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 109.3 %

Procedure:
A 500 mL round-bottom flask was charged with diisopropylamine (12.89 mL, 92.00 mmol) and dry THF (100 mL) and cooled to −78° C. Butyllithium (2.5 M in hexanes) (36.80 mL, 92.00 mmol) was added dropwise over 20 minutes and the mixture was agitated for additional 30 minutes. Methyl 2-methoxypropanoate (10.35 g, 87.61 mmol) was added dropwise over 20 minutes and the mixture was agitated for 30 minutes. 2,3-Dibromopropene (10.70 mL, 87.61 mmol) was added dropwise over 20 minutes, the mixture was agitated for 30 minutes and then allowed to warm up to ambient temperature and agitated for additional 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ether. Extracts were washed with sodium bicarbonate solution, brine, dried and evaporated to give the title compound (22.7 g, 98.4% yield) as pale yellow oil.
Reaction SMILES: C(O)C#C.[CH2:5]([OH:17])[C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CCOCC.COCCO[AlH2-]OCCOC.[Na+]>[CH2:5]([OH:17])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCC#CCO
Agent: C#CCO
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCC/C=C/CO

Procedure:
trans-2-Dodecen-1-ol was prepared by reduction of the propargyl alcohol by the method described by Jones and Denmark (Org. Syn., 1985, 64, 182-8) using 6.0 g (33 mmole) of 2-dodecyn-1-ol in 25 ml of ether and 16.2 ml of Red-Al in 30 ml of ether. Kugelrohr distillation afforded 5.73 g of a clear oil. 1H NMR δ 5.66 (m, 2), 4.07 (d, 2, J=4 Hz), 2.03 (dd, 2, J=6, 13 Hz), 1.62 (br, 1), 1.4-1.2 (m, 14), 0.88 (t, 3, J=7 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:17]=O)[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.[C-]#N.[Li+].O1CCCC1.[C:27](P(=O)(OCC)OCC)#[N:28].C(O)(C)(C)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH2:17][C:27]#[N:28])[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1
Reactant: O=Cc1cc(OC2CCCCO2)cc2ccoc12
Reactant: CCOP(=O)(C#N)OCC
Agent: [C-]#N
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: N#CCc1cc(OC2CCCCO2)cc2ccoc12
Reaction time: 0.33 h

Procedure:
Combine 5-(tetrahydropyran-2-yloxy)benzofuran-7-carboxaldehyde (3.75 g, 0.015 mol) with lithium cyanide-tetrahydrofuran (1:1.5 complex, 0.215 g, 0.1 equivalent) in tetrahydrofuran (80 mL) under nitrogen. Add diethyl cyanophosphonate (3.0 mL, 1.3 equivalents) and stir at 20° C. for 2 days. Add tert-butanol (1.6 mL, 1.1 equivalents) then SmI2 in tetrahydrofuran (0.1 M solution, approximately 400 mL). Concentrate the solution in vacuo then redissolve in a solution of ethyl acetate:diethyl ether (approximately 3:1, 100 mL). Add saturated aqueous ammonium chloride and stir for 20 min, until the release of hydrogen cyanide is complete. Filter to remove insoluble material, then extract against 1 N hydrochloric acid. Dry over sodium sulfate, then filter and concentrate. Purification by a plug column (4:1 hexanes:ethyl acetate) to provide the title compound as a light yellow oil.
Reaction SMILES: [CH:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])([CH2:3][CH3:4])[CH3:2].[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17](Cl)=[O:18])[CH:14]=[CH2:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH:1]([CH2:3][CH3:4])[CH3:2])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCC(C)S(=O)(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)C(C)CC)n1
Temperature: 95 °C

Procedure:
A mixture of 9.5 g. 3-sec.butylsulphonyl-1,2,4-triazole, 7.97 g. diallylcarbamoyl chloride, 50 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 5 hours. The reaction mixture was worked up by a method analogous to that described in Example 1 to give an oil which was not distilled but was heated under reduced pressure (95° C./0.1 mm.) for 4 hours to remove traces of volatile material. The resulting product, 1-diallylcarbamoyl-3-sec.butylsulphonyl-1,2,4-triazole, was obtained as an oil, nD26 1.5174. (98.9% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: Cl[C:2]1[C:3](=[O:22])[C:4](=[O:21])[C:5]=1[C:6]1[CH:7]=[C:8]([CH3:20])[C:9]2[C:15]=1[C:14]([CH3:16])=[CH:13][CH:12]=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=2.[OH2:23].Cl>O1CCOCC1>[OH:23][C:2]1[C:3](=[O:22])[C:4](=[O:21])[C:5]=1[C:6]1[CH:7]=[C:8]([CH3:20])[C:9]2[C:15]=1[C:14]([CH3:16])=[CH:13][CH:12]=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=2
Reactant: O
Reactant: Cc1cc(-c2c(Cl)c(=O)c2=O)c2c(C)ccc(C(C)C)cc1-2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2c(O)c(=O)c2=O)c2c(C)ccc(C(C)C)cc1-2
Yield: 62 %

Procedure:
62.4 g (0.2 mol) of 3-chloro-4-(7-isopropyl-1,4-dimethyl-3-azulenyl)cyclobut-3-ene-1,2-dione were refluxed in 200 ml of dioxane, 40 ml of water and 2 ml of concentrated hydrochloric acid for 8 hours. The solvent was removed under reduced pressure, and the remaining oily residue was crystallized by adding dichloromethane. 36.5 g (62%) of 3-hydroxy-4-(7-isopropyl-1,4-dimethyl-3-azulenyl)cyclobut-3-ene-1,2-dione were obtained as dark brown crystals of melting point 120°-123° C. The substance was used without further purification for synthesizing dyes.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=2)[CH2:8][CH2:7]1.CCN(CC)CC.[SH2:32].CC[O-].[Na+].C(O)C>O1CCOCC1>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17](=[S:32])[NH2:18])=[CH:15][N:16]=2)[CH2:8][CH2:7]1
Reactant: N#Cc1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Reactant: S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NC(=S)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carbonitrile (354 mg, 1.0 mmol) in dioxane was added Et3N (20 μL, 0.14 mmol) and H2S (gas) was bubbled through the solution for about 1 min. After stirring at room temperature for 3 h, ethanol was added, followed by 21 wt. % NaOEt in ethanol (238 μL, 0.6 mmol). More H2S (gas) was bubbled through the solution for another minute. The mixture was then stirred at room temperature for 3 days. Volatile materials were removed in vacuo. The residue was dissolved in EtOAc, washed twice with water, dried (Na2SO4) and concentrated. Trituration with Et2O gave the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[S:9](=[O:12])(=[O:11])=[O:10]>C(OC)(=O)C(C)=C>[S:9]([C:2]1([CH3:1])[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4])([OH:12])(=[O:11])=[O:10]
Reactant: O=S(=O)=O
Reactant: CC1CC(=O)OC1=O
Agent: C=C(C)C(=O)OC
Product: CC1(S(=O)(=O)O)CC(=O)OC1=O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
114 g. of methyl-succinic anhydride and 80 g. of liquid sulfur trioxide are stirred and heated to 110° C. in an apparatus fitted with a condenser adequate to contain the low boiling sulfur trioxide. After 1 hour, the product is cooled to 25° C. and has an equivalent weight of about 65. It is stored as a solution in methyl methacrylate.