Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16].[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C(O)(=O)C>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:16]([C:15]1[CH:17]=[CH:18][C:19]([CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=1)[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[Cl:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Clc1nc2ccccc2s1
Reactant: COc1cc(N)ccc1C
Solvent: CC(=O)O
Product: COc1cc(N(C(=O)c2ccccc2Cl)c2nc3ccccc3s2)ccc1C
Temperature: 115 °C

Procedure:
A mixture of 0.339 g (2 mmol) 2-Chlorobenzthiazole (commercially available) and 0.275 g (2 mmol) 3-methoxy-4-methylaniline (commercially available) in 4 ml acetic acid was heated to 115° C. for 4 h. After cooling to room temperature the mixture was subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. The product fractions of Benzothiazol-2-yl-(3-methoxy-4-methyl-phenyl)-amine were evaporated to dryness and reacted according to the procedure described for Example 2 with 2-chlorobenzoyl chloride to yield the title compound. MS (m/e): 409.3 (MH+, 100%). According to the procedure described for Example 35 further N-Benzothiazol-2-yl-N-(aryl)-benzamide derivatives have been synthesised by reaction of 2-chlorobenzthiazole with the respective aniline (commercially available) and subsequently with the respective acid chloride. The results are shown in table 2 below and comprise Example 36 to Example 43.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH2:10]Cl.[C:24]([O:34][CH2:35][CH3:36])(=[O:33])[CH:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[OH:26].C(N(CC)CC)C.CC(C)=[O:46]>O>[CH2:35]([O:34][C:24]([CH:25]([O:26][C:10](=[O:46])[C:9]1[CH:12]=[C:5]([O:4][C:3]2[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:33])[CH3:36]
Reactant: CC(C)=O
Reactant: CCOC(=O)CC(O)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(OC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCC

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzyl chloride (3.8 g, 0.01 mole) in acetone (10 ml) was successively added diethyl DL malate (1.9 g, 0.01 mole) in acetone (10 ml) and triethylamine (1.01 g, 0.01 mole) in acetone (5 ml). A white precipitate quickly formed. The reaction was heated to reflux for 24 hours. Upon cooling, the reaction was poured in water (75 ml) and extracted twice with methylene chloride (25 ml@). The combined organic extracts were successively washed with 5% sodium hydroxide and brine solutions. The dried solution was stripped of solvent to give 3.5 g of an amber oil.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:9])[C:6]=1[CH:7]=[O:8].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=O)=[O:19])=[CH:14][CH:13]=1)#[CH:11].C([N:24](CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH:7]([C:6]1[N:5]([CH3:9])[N:4]=[CH:3][C:2]=1[C:11]#[C:10][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:24])(=[O:21])=[O:19])=[CH:14][CH:13]=1)=[O:8]
Reactant: Cn1ncc(I)c1C=O
Reactant: CCN(CC)CC
Reactant: C#Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: Cn1ncc(C#Cc2ccc(S(N)(=O)=O)cc2)c1C=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-iodo-1-methyl-1H-pyrazol-5-carbaldehyde (500 mg), 4-ethynylbenzenesulfonic acid (383 mg), copper(I) iodide (20 mg), bis(triphenylphosphine)palladium(II) dichloride (149 mg), triethylamine (600 μL) and dimethylformamide (10 mL) was stirred at 80° C. for 4 hours. Thereafter, the reaction solution was filtrated with Celite, and the filtrate was then washed with water. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform/methanol=99:1 to 90:10), so as to obtain the title compound (580 mg) in the form of a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]([C:11]([O:13]C)=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.O[Li].O>C1COCC1.CO.O.O>[Br:1][C:2]1[S:3][C:4]2[CH:10]([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: COC(=O)C1CCCc2nc(Br)sc21
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCc2nc(Br)sc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of methyl 2-bromo-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxylate (150 mg, 0.54 mmol) and LiOH.H2O (34 mg, 0.81 mmol) in THF/MeOH/H2O (5 mL, 3:1:1) was stirred at RT for 90 min. The mixture was diluted with H2O and extracted with DCM. The aq. layer was acidified to pH=3 and extracted with DCM. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:57]([O:61][C:62](=[O:78])[CH2:63][CH2:64][C:65]1[C:70]([CH3:71])=[CH:69][C:68]([C:72](=[NH:75])[NH:73]O)=[CH:67][C:66]=1[CH2:76][CH3:77])([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C.O1CCOCC1>[C:57]([O:61][C:62](=[O:78])[CH2:63][CH2:64][C:65]1[C:70]([CH3:71])=[CH:69][C:68]([C:72]2[N:73]=[C:11]([C:8]3[CH:7]=[C:6]([CH3:14])[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:10][N:9]=3)[O:13][N:75]=2)=[CH:67][C:66]=1[CH2:76][CH3:77])([CH3:60])([CH3:59])[CH3:58]
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Reactant: Cc1cc(C(=O)O)ncc1CC(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 5-isobutyl-4-methyl-pyridine-2-carboxylic acid (246 mg, 1.07 mmol) and DIPEA (415 mg, 3.21 mmol) in DMF (4 mL), PyBOP (589 mg, 1.13 mmol) is added at 0° C. The mixture is stirred for 15 min at 0° C. before 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester (328 mg, 1.07 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched by adding water, the mixture is diluted with sat. aq. NaHCO3-solution and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxy-amidine ester intermediate; LC-MS: tR=1.10 min, [M+H]+=482.27. This material is dissolved in dioxane (10 mL) and the mixture is stirred at 80° C. for 15 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid tert-butyl ester (420 mg) as a colourless oil; LC-MS: tR=1.26 min, [M+H]+=464.34.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([S:25]([CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])(=[O:27])=[O:26])[CH:20]=[CH:19]2)=O)C>C1(C)C=CC=CC=1>[CH3:31][Si:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][S:25]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([CH2:14][OH:13])=[CH:24][CH:23]=2)[CH:19]=[CH:20]1)(=[O:27])=[O:26]
Reactant: CCOC(=O)c1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(CO)ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of diisobutylaluminum hydride (82.9 mL, 1M in toluene, 82.9 mmol) was added slowly at 0° C. to the solution of 1-(2-trimethylsilanylethanesulfonyl)-1H-indole-5-carboxylic acid ethyl ester (8.81 g, 25.9 mmol) in toluene (200 mL). After it was stirred at 0° C. for 45 min, the reaction was quenched by the addition of methanol (26 mL), pulverized sodium sulfate decahydrate (194 g) and celite (26 mL). The mixture was warmed up to room temperature in 1 h and filtered through a pad of celite. Solvents were removed in vacuo to afford the title compound as a very viscous liquid, which solidified upon cooling. A white solid (8.08 g, 100% yield). 1H-NMR (CDCl3, 500 MHz) δ 7.87 (d, J=8.5 Hz, 1H), 7.62 (s, 1H), 7.44 (d, J=3.7 Hz, 1H), 7.35 (dd, J=8.6, 1.5 Hz, 1H), 6.66 (d, J=3.7 Hz, 1H), 4.79 (s, 2H), 3.18-3.14 (m, 2H), 1.73 (s, 1H), 0.85-0.82 (m, 2H), −0.06 (s, 9H). Mass spec. 312.14 (MH)+.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([OH:22])=O)[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[S:30]1[C:34]2[CH2:35][CH2:36][CH2:37][C:33]=2[N:32]=[C:31]1[NH2:38].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][O:23][C:5]1[C:4]([O:3][CH:2]([F:29])[F:1])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:10]=[CH:11]/[C:12]1[N:13]=[C:14]2[N:18]([C:19]=1[C:20]([NH:38][C:31]1[S:30][C:34]3[CH2:35][CH2:36][CH2:37][C:33]=3[N:32]=1)=[O:22])[CH:17]=[CH:16][S:15]2
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: Nc1nc2c(s1)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc3c(s2)CCC3)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine (37 mg, 0.260 mmol) in the presence of EDCI hydrochloride (91 mg, 0.472 mmol) and DMAP (26 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 20 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 2.42-2.52 (m, 2H), 2.75-2.81 (m, 4H), 3.58 (s, 2H), 7.18 (t, J=76.2 Hz, 1H), 7.20-7.28 (m, 2H), 7.38-7.45 (m, 1H), 7.71 (d, J=6.9 Hz, 1H), 7.84 (d, J=15.9 Hz, 1H), 8.05-8.12 (m, 1H), 8.46-8.53 (m, 1H), 13.03 (br s, 1H); APCI-MS (m/z) 545.53 (MH)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH2:3][CH2:2]1.[S:14]1[CH2:20][C:18](=[O:19])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1=[S:16].[Cl-].[NH4+].N>C(O)C>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[C:20]3[S:14][C:15](=[S:16])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18]3=[O:19])[N:11]=2)[CH2:5][CH2:6]1
Reactant: O=Cc1csc(N2CCOCC2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(N3CCOCC3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 1.65 g of 2-morpholinothiazole-4-carbaldehyde, 1.3 g of rhodanine-3-acetic acid, 1g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 35 ml of ethanol, giving the title compound as yellow needles.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.CN1CCOCC1.[CH2:18]([O:25][CH2:26][C:27](Cl)=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C=O)C>[CH2:18]([O:25][CH2:26][C:27]([NH:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1)=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Cc1nc(N)sc1C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)COCc2ccccc2)sc1C(=O)O
Temperature: 80 °C

Procedure:
300 mg (1.90 mmol) 2-Amino-4-methylthiazole-5-carboxylic acid and 0.67 mL (6.07 mmol) N-methylmorpholine are added to 20 mL DMF. After adding 0.32 mL (2.09 mmol) benzyloxyacetyl chloride the resulting mixture is stirred at 80° C. over night. Then the mixture is callowed to cool to r.t. and slightly acidified with aq. HCl solution (c=1 mol/L). The solvent is removed in vacuo, water is added and the suspension is stirred for 10 min before the precipitate is filtered off and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[N:6]=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[NH:6][CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][N:14]=[C:7]1[NH:6][CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)nc1nccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1)NC1=NCCN12
Product: Clc1ccc2c(c1)C(c1ccccc1)Nc1nccn1-2
Temperature: 0 °C

Procedure:
To a suspension of 0.28 g of 7-chloro-5-phenylimidazo[1,2-a]quinazoline in 20 ml of ethanol was added 0.2 g of sodium borohydride, and the mixture was heated under reflux for 10 hours. After cooling, the mixture was poured into ice-water, and the resulting precipitate was collected by filtration, washed with water and dried. The product was dissolved in chloroform and absorbed on an activated alumina column. Elution with chloroform and recrystallization from ethanol gave 7-chloro-4,5-dihydro-5-phenylimidazo[1,2-a]quinazoline (m.p. 239°-241° C.) and 7-chloro-1,2,4,5-tetrahydro-5-phenylimidazo[1,2-a]quinazoline (m.p. 210°-213° C.).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([S:10]C#N)[CH:7]=[CH:6][C:5]=1[OH:13].[CH3:14][C:15]1[CH:16]=[C:17]([S:26]CC2SC(C3C=CC(C(F)(F)F)=CC=3)=NC=2C)[CH:18]=[CH:19][C:20]=1[O:21]CC(O)=O.Cl>O.CCOCC>[C:15]1([CH3:14])[C:20]([OH:21])=[CH:19][CH:18]=[C:17]([S:26][S:10][C:8]2[CH:9]=[C:4]([CH3:3])[C:5]([OH:13])=[CH:6][CH:7]=2)[CH:16]=1
Reactant: Cc1cc(SC#N)ccc1O
Reactant: Cc1cc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(SSc2ccc(O)c(C)c2)ccc1O
Temperature: 95 °C

Procedure:
To a stirred solution of 33.0 g (825.6 mmol) NaOH in 200 ml water was added 44.0 g (266.3 mmol) of 2-methyl-4-thiocyanato-phenol at 85° C. [Wei, Zhi-Liang; Kozikowski, Alan P., A Short and Efficient Synthesis of the Pharmacological Research Tool GW501516 for the Peroxisome Proliferator-Activated Receptor delta, Journal of Organic Chemistry (2003), 68(23), 9116-9118]. The temperature was raised to 95° C. and the mixture stirred over night. After cooling (10° C.), ether and 90 ml of aqueous conc. HCl were added. The water phase was extracted with ether (two times). The organic phase was washed with brine, dried (Na2SO4) and evaporated. The residue was dissolved in 300 ml of DMSO and heated for 2 h at 95° C. Subsequently, the solution was poured onto ice water and extracted with three 1 l portions of TBME. The organic layers were washed with 700 ml of water, dried (Na2SO4) and evaporated to give 42.1 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([Cl:24])=[O:23]>O1CCOCC1>[ClH:24].[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[N:3]=1)=[O:23]
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Solvent: C1COCCO1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3OC(F)(F)F)n2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.18 g, 0.84 mmol), 2-trifluoromethoxybenzoyl chloride (0.23 g, 1.0 mmol) and 1,4-Dioxane (5 mL). Stir and heat the mixture at reflux. After 3 hr., cool the reaction mixture to ambient temperature. Load on an SCX column (10 g), wash with methanol, and elute with 2M ammonia/methanol. Concentrate the eluent to obtain the free base of the title compound (0.26 g, 76%). Dissolve the free base in methanol (10 mL) and treat with ammonium chloride (0.032 g). Concentrate and dry under vacuum to obtain the title compound. HRMS Obs. m/z 408.1517, Calc. m/z 408.1535; m.p. 155-160° C.
Reaction SMILES: NC1S[C:4]([CH:9]=[O:10])=[CH:5][C:6]=1[C:7]#[N:8].C(CC[N:15](CC)[C:16]1[CH:21]=[CH:20]C=C(C)C=1)#N.C(O)(=[O:27])C>>[C:16]([CH2:21][C:20]([O:10][CH2:9][CH3:4])=[O:27])#[N:15].[NH:8]1[CH2:9][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N#Cc1cc(C=O)sc1N
Reactant: CCN(CCC#N)c1cccc(C)c1
Reactant: CC(=O)O
Product: C1CCNCC1
Product: CCOC(=O)CC#N

Procedure:
Using a method similar to that described in Example 1(a), 7.6 parts of 2-amino-3-cyano-5-formylthiophene were reacted with 9.7 parts of N-cyanoethyl-N-ethyl-m-toluidine to give 13 parts of the dye of the formula ##STR19## 3.8 parts of ethyl cyanoacetate, 1.5 parts of glacial acetic acid and 1.5 parts of piperidine were added to 6.0 parts of this dye in 45 parts by volume of dioxane, and the mixture was stirred for 16 hours at room temperature. Thereafter, the dye was precipitated by adding 50 parts of water and 50 parts of ice, the mixture was stirred for 1 hour and the product was filtered off under suction, washed neutral with water and dried to give 7 parts of the dye of the formula ##STR20## which dyes polyesters in fast dark blue hues.
Reaction SMILES: C(O)C.[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1)#[N:5].Cl.[NH2:17][OH:18].[OH-].[Na+]>ClCCCl.O>[F:14][C:12]([F:15])([F:13])[C:9]1[CH:10]=[CH:11][C:6]([C:4](=[N:17][OH:18])[NH2:5])=[N:7][CH:8]=1
Reactant: N#Cc1ccc(C(F)(F)F)cn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
180 ml of ethanol were added to a solution of 22 g of 2-cyano-5-trifluoromethylpyridine in 180 ml of 1,2-dichloroethane under stirring at room temperature, followed by drop-wise addition thereto of a solution of 9.8 g of hydroxylamine hydrochloride in 17 ml of water. An aqueous solution of 5.6 g of sodium hydroxide in 17 ml of water was drop-wise added to the resulting mixture. After completion of the drop-wise addition, the reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was cooled, and stripped of insolubles by filtration. The filtrate was subjected to distillation under reduced pressure to remove therefrom the solvent. The resulting residue was washed with hexane. The precipitated solid was filtered off to obtain 25 g of 5-trifluoromethyl-2-pyridinecarboxamide oxime having a melting point of 130° to 133° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:23]
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Br)c1
Reaction time: 21 h
Yield: 74.4 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-chlorophenyl isocyanate (0.29 ml, 2.40 mmol) in THF (2 ml) was added Et3N (33 ml, 0.24 mmol) at room temperature. After 21 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-chlorophenyl)ureido]phenylacetate (710 mg, 74%) as a pale brown powder. 1H-NMR (CDCl3) δ3.57 (s, 2H), 3.70 (s, 3H), 7.02-7.28 (m, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.48 (s, 1H), 8.00-8.11 (m, 2H); MS (ESI) m/z 397 (M+), 399 (M++2), 401 (M++4).
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1.[C:16](OCC)(=[O:23])[CH2:17][C:18](OCC)=[O:19]>CO.C(O)C>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]2[N:13]=[C:18]([OH:19])[CH:17]=[C:16]([OH:23])[N:12]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C(=N)N)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COc1ccc(-c2nc(O)cc(O)n2)cc1
Yield: 83.9 %

Procedure:
338 g of a 30% solution of sodium methylate in methanol are added over 10 minutes to a suspension of 112 g of p-methoxybenzamidine hydrochloride and 101 g of diethyl malonate in 520 ml of ethanol, and the mixture is subsequently refluxed for 5 hours. The reaction mixture is then concentrated by rotary evaporation and the residue is dissolved in 1000 ml of warm water of 80° C. The solution is filtered and the filtrate is acidified to pH 1. The precipitate is isolated by filtration and vacuum dried at 80° C., affording 109.8 g of 2-p-methoxyphenyl-4,6-dihydroxypyrimidine with a melting point of 318° C. (decompos.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.O[CH2:35][CH2:36][CH2:37][C@@H:38]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:39][C:40]([O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[O:41]>C(Cl)Cl>[Br:1][CH2:35][CH2:36][CH2:37][C@@H:38]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:39][C:40]([O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[O:41]
Reactant: CC(C)(C)OC(=O)[C@H](CCCO)NC(=O)OCC[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@H](CCCBr)NC(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-bromosuccinimide (2.129 g, 11.96 mmol) in DCM (10 ml) was treated with triphenylphosphine (2.93 g, 11.17 mmol) in DCM (10 ml), followed by pyridine (0.387 ml, 4.79 mmol) and tert-butyl 5-hydroxy-N-{[2-(trimethylsilyl)ethoxy]carbonyl}-L-norvalinate (1.33 g, 3.99 mmol) in DCM (5 ml). The resulting black mixture was stirred at room temp for 24 h. The mixture was pre-absorbed onto SiO2 and purified by chromatography (silica gel, 0-5-10-20% Et2O/isohexane) to afford tert-Butyl 5-bromo-N-{[2-(trimethylsilyl)ethoxy]carbonyl}-L-norvalinate Intermediate 5 (1.1 g) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O1CCCC1>CO.[Pd].[H][H]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Yield: 99.7 %

Procedure:
To a solution of 2.54 g of tert-butyl 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1-carboxylate (which was prepared by the method as described in Synthesis, 1991, 993-995) in 20 ml of methanol, 250 mg of 10% palladium-on-carbon catalyst was added, and stirred for an hour in hydrogen atmosphere at ambient temperature and pressure. After addition of 20 ml of tetrahydrofuran to the reaction liquid, the liquid was filtered with Celite. Distilling the solvent off under reduced pressure, 2.30 g of the title compound was obtained.
Reaction SMILES: [OH-].[Na+].C(OC([O-])=O)(O[C:6](C)([CH3:8])[CH3:7])=O.C1C2[CH:21]=[C:22]([OH:25])[CH:23]=CC=2CCCN1.[C:26]([O:29][CH2:30][CH3:31])(=[O:28])[CH3:27]>C(Cl)(Cl)Cl.O>[C:26]([O:29][CH2:30][CH3:31])(=[O:28])[CH3:27].[CH:6]([O:25][CH:22]([CH3:21])[CH3:23])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Oc1ccc2c(c1)CNCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)OC(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 N sodium hydroxide (40 ml) and t-butyl dicarbonate were added at 0° C. to a solution of 2,3,4,5-tetrahydro-1H-2-benzazepin-8-ol hydrobromate (12.0 g, 49.2 mm) in chloroform (40 ml) and water (40 ml), and the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the resulting mixture which was then washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resultant residues were formed into powder with ethyl acetate-isopropyl ether, to give the title compound (7.99 g).