Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1(CO)[CH2:6][O:5][CH2:4]1)[CH3:2].C(N([CH2:14][CH3:15])CC)C.[C-]#N.[Na+].CC(C[AlH]CC(C)C)C.CS(C)=[O:30]>ClCCl>[CH2:1]([C:3]1([CH2:14][CH:15]=[O:30])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CO)COC1
Reactant: CS(C)=O
Reactant: CCN(CC)CC
Agent: CC(C)C[AlH]CC(C)C
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Product: CCC1(CC=O)COC1

Procedure:
Step A In a manner similar to the methods described in Example 112a Step A. Step B., and Step C., 3-ethyl-3-oxetanemethanol (TCI-US) (3.5 g, 30 mmol) was reacted with triethylamine (6.6 g, 60 mmol) and treated with NaCN (2.2 g, 46 mmol) in anhydrous dimethyl sulfoxide at 130° C., followed by the reaction with DIBAL (1 M in heptane, 27 mL, 27 mmol) in dichloromethane at 0° C. to give (3-ethyl-oxetan-3-yl)-acetaldehyde as a light yellow oil (Yield: 2.5 g, 26% for three steps).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].Cl.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1>O>[C:10]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1
Reactant: NCCC(=O)O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCNC(=O)c1cccnc1
Reaction time: 5 h
Yield: 96.5 %

Procedure:
Ten grams of β-alanine and 9 g of sodium hydroxide were dissolved in 100 mL of purified water, and 18.15 g of nicotinoyl chloride hydrochloride were added dropwise under freezing conditions. After stirring for five hours, the product was filtered, the resulting crude product was recrystallized with aqueous ethanol, and 19.1 g of the desired product was obtained (yield of 84%).
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)[C:6](=[O:27])[C:5]=1O)(=O)[CH3:2].[NH:29]([C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1)[NH2:30]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:30][N:29]([C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)[C:5]=3[C:6](=[O:27])[N:7]2[C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Reactant: Cn1nccc1NN
Product: Cc1nn(-c2ccnn2C)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 90.1) and 5-hydrazinyl-1-methyl-1H-pyrazole (Step 74.2). The crude material was purified by silica gel column chromatography (1% ammonia/7.5% MeOH/CH2Cl2) and triturated in Et2O. tR: 0.92 min (LC-MS 2); ESI-MS: 473 [M+H]+ (LC-MS 2); Rf=0.34 (1% ammonia/7.5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.06 (s, 3H) 2.43 (s, 3H) 2.60 (s, 3H) 3.85 (s, 3H) 6.55 (s, 1H) 6.58-6.68 (m, 1H) 7.31 (s, 1H) 7.37 (m, J=8.6 Hz, 2H) 7.45 (m, J=8.6 Hz, 2H) 7.56 (d, J=2.4 Hz, 1H) 8.44 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.[N+:26]([O-])([OH:28])=[O:27]>>[F:1][C:2]([F:17])([F:18])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][C:10]=1[N+:26]([O-:28])=[O:27]
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 24 h

Procedure:
To 58.1 g. (0.212 mole) of 1,4-bis(2,2,2-trifluoroethoxy)benzene in 400 ml. of trifluoroacetic acid is added dropwise with stirring 13.7 ml. of concentrated nitric acid over 3.5 hours at 25°±2° C. Stirring is continued for 24 hours, then the mixture is concentrated to one-third the original volume. The concentrate is poured into 600 ml. of water, and the resulting solution is extracted twice with diethyl ether. The ether solution is washed thrice with saturated sodium chloride solution, then with dilute sodium hydroxide solution until the washings are basic. The solution is washed again with saturated sodium chloride solution, dried and evaporated. The liquid residue is distilled to provide 2,5-bis(2,2,2-trifluoroethoxy)nitrobenzene as a clear, pale yellow liquid, b.p. 116°-119° C./0.35 mm Hg.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>[Br-].C([N+](CC)(CC)CC)C.O>[C:1]([O:8][CH2:9][CH:11]1[O:13][CH2:12]1)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6]
Reactant: C/C=C/C=C/C(=O)O
Reactant: ClCC1CO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: O
Product: C/C=C/C=C/C(=O)OCC1CO1
Temperature: 110 °C

Procedure:
To 1.8 g of sorbic acid (manufactured by Wako Pure Chemical) were added 1 g of tetraethylammonium bromide (manufactured by Wako Pure Chemical) and 60 ml of epichlorohydrin (manufactured by Wako Pure Chemical), the mixture was heated to reflux at 110° C. for 3 hours, 30 ml of distilled water was added thereto and an organic layer was separated and concentrated in vacuoat 80° C. to give 3.5 g of glycidyl sorbate. An epoxy equivalent of this glycidyl sorbate was 367.4.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CO[C:17]1[C:21](OC)=[N:20][S:19](=[O:24])[N:18]=1.[CH2:25]([NH2:27])[CH3:26]>CO>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[C:21]([NH:27][CH2:25][CH3:26])=[N:20][S:19](=[O:24])[N:18]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: COC1=NS(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CCN
Solvent: CO
Product: CCNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.64 g; 12.3 mmoles) in 25 ml of dry methanol was added dropwise over a period of 30 minutes to a well stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.0 g; 12.3 mmoles) in 75 ml of dry methanol that had been cooled to 8° in an ice-water bath. After 15 minutes, 4.0 ml of ethylamine was added and the mixture stirred at ambient temperature for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue placed on 55 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined, evaporated under reduced pressure and the residue treated with ether and decanted. The residue was treated with fresh ether to give 1.5 g of the title compound, mp 68°-74°.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[C:12]([S:14][CH3:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>C(O)(=O)C.CN(C)C=O.[Fe]>[CH3:15][S:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][CH:11]=1)[N:16]=[C:1]([NH2:2])[C:3]([C:4]([NH2:6])=[O:5])=[CH:7]2
Reactant: CSc1ccc([N+](=O)[O-])c(C=C(C#N)C(N)=O)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CSc1ccc2nc(N)c(C(N)=O)cc2c1
Temperature: 75 °C

Procedure:
A mixture of α-cyano-β-(2-nitro-5-methylthiophenyl)acrylamide (8.4 g., 0.032 mole) in acetic acid - N,N-dimethylformamide (110 ml. of 1:1) is heated in a 75° C. bath. Iron powder (2.0g.) is added and the mixture stirred until the internal temperature rose to 95° C. Additional iron powder (6.16 g. total iron added = 0.146 mole) is added in small portions over a 15-minute period. The reaction mixture is stirred for 1 hour following completion of addition and then filtered hot. The iron residue is washed with hot acetic acid and the combined filtrate and wash solution poured into IN hydrochloric acid (200 ml.). The hydrochloride salt which separates is filtered off and dissolved in hot dilute aqueous sodium hydroxide. The yellow solid which separates on cooling is filtered off, washed with isopropyl alcohol and air-dried. Yield = 3.26 g. (44%); M.P. 229°-242° C.
Reaction SMILES: [Br:1]C=CBr.[Mg:5].[CH3:6][C:7]1([CH2:15][CH2:16]Br)[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8]1>O1CCCC1>[Br:1][Mg:5][CH2:16][CH2:15][C:7]1([CH3:6])[O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12]1
Reactant: CC1(C)COC(C)(CCBr)OC1
Reactant: BrC=CBr
Reactant: [Mg]
Solvent: C1CCOC1
Product: CC1(C)COC(C)(CC[Mg]Br)OC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, 5 ml of tetrahydrofuran and 0.1 ml of dibromoethylene were added to 3.4 g of metallic magnesium, the mixture was ice-cooled, and 30.0 g of 2,5,5-trimethyl-2-(2-bromoethyl)-1,3-dioxane and 75 ml of tetrahydrofuran were added dropwise to that mixture simultaneously over 1.5 hours. After completion of the dropping, the mixture was stirred for 1 hour with ice cooling and further at room temperature for 30 minutes to give bromo[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]magnesium (1.16 mol/l, tetrahydrofuran solution).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([S:11]([NH:14][CH:15]([CH2:29][C:30]2[CH:38]=[CH:37][C:36]([O:39]C)=[C:35]3[C:31]=2[CH:32]=[CH:33][NH:34]3)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:41][CH2:42]S.[NH4+:44].[Cl-]>>[C:5]1([S:11]([NH:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH:21]([C:42]2[CH:41]=[CH:37][C:36]([OH:39])=[C:35]3[C:31]=2[CH:30]=[CH:29][NH:44]3)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])(=[O:12])=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[C:5]1([S:11]([NH:14][CH:15]([CH2:29][C:30]2[CH:38]=[CH:37][C:36]([OH:39])=[C:35]3[C:31]=2[CH:32]=[CH:33][NH:34]3)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: CCS
Reactant: COc1ccc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cc[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CNS(=O)(=O)c1ccccc1)NCCC(Cc1ccccc1)c1ccc(O)c2[nH]ccc12
Product: O=C(NCCCCc1ccccc1)C(Cc1ccc(O)c2[nH]ccc12)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Aluminum chloride (0.13 g, 0.99 mmol) is added to a 0° C. solution of 2-benzenesulfonylamino-3-(7-methoxy-1H-indol-4-yl)-N-(4-phenyl-butyl)-propionamide (0.12 g, 0.25 mmol) and EtSH (0.061 g, 0.99 mmol). The mixture is stirred 3.5 h while being allowed to warm to rt. Additional AlCl3 (0.13 g, 0.99 mmol) and EtSH (0.061 g, 0.99 mmol) are added and the mixture is stirred 1 h more. The mixture is then poured into a saturated NH4Cl solution and extracted twice with EtOAc. The organics are dried (MgSO4) and concentrated. The crude residue is purified by column chromatography (silica, 1:3 EtOAc/CH2Cl2) to provide the title compound 2-benzenesulfonylamino-3-(7-hydroxy-1H-indol-4-yl)-N-(4-phenyl-butyl)-propionamide as an oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:18])[CH2:16]Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20]1[O:25][CH:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>[OH-].[Na+]>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:18])[CH2:16][N:22]2[CH2:21][CH:20]([CH3:19])[O:25][CH:24]([CH3:26])[CH2:23]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=Cc1cccc(Oc2ccccc2)c1)CBr
Reactant: CC1CNCC(C)O1
Agent: [Na+]
Agent: [OH-]
Product: CC(=Cc1cccc(Oc2ccccc2)c1)CN1CC(C)OC(C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
3-(m-Phenoxyphenyl)-2-methyl-2-propenyl bromide (1.0 g) was added to 2,6-dimethylmorpholine (2.0 g) at 0° C. while stirring, followed by aging at the same temperature for 3 hours. Ice water (100 ml) and 15% aqueous sodium hydroxide solution (30 ml) were added to the resultant mixture to make basic, followed by extraction with ethyl acetate (50 ml×3). The extracts were combined together, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-[3-(m-phenoxyphenyl)-2-methyl-2-propenyl]-2,6-dimethylmorpholine (cis-isomer, 0.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[S:7][C:6]=2[C:17]=1[Cl:18].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2cc(-c3ccccc3F)sc2c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1cc2cc(-c3ccccc3F)sc2c(Cl)c1Cl
Yield: 86.2 %

Procedure:
A mixture of 16.0 g of 6,7-dichloro-5-methoxy-2-(2'-fluorophenyl)benzo[b]thiophene and 150 g of pyridine hydrochloride is heated at 200°-250° for 1 hour with stirring under an atmosphere of nitrogen. The mixture is allowed to cool, diluted with water and the precipitate is collected. The precipitate is dissolved in dichloromethane and the solution is washed with water, dried and filtered. Evaporation of the solvent followed by treatment of the mixture with ether-hexane gives 13.2 g of 6,7-dichloro-2-(2'-fluorophenyl)-5-hydroxybenzo[b]thiophene as an amorphous solid.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](O)=[N:12][N:11]=[CH:10]2.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[C:14]2[C:9](=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:18])=[CH:16][CH:15]=2)[CH:10]=[N:11][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1-c1ccc2c(O)nncc2c1
Product: Cc1ccccc1-c1ccc2c(Cl)nncc2c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 6-o-tolylphthalazin-1-ol (3.65 g, 15 mmol) and phosphorus oxychloride (15 mL, 161 mmol) was stirred at 110° C. for 16 h. After cooling to RT, the phosphorus oxychloride was removed in vacuo. The residue was diluted with ethyl acetate (100 mL) and washed with saturated aqueous Na2O3 and brine. The organic solution was dried over magnesium sulfate, and concentrated under reduced pressure. Flash chromatography on silica gel (ethyl acetate: hexane 60:40) gave 1-chloro-6-o-tolylphthalazine as a yellow solid. MS (ESI, pos.ion) m/z: 255.0 (M+1)
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1F.COC1C=CC(CN2C(=O)C(C)NC2=O)=CC=1.[CH3:42][C:43]1[C:44]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([C:58]3[CH:63]=[CH:62][C:61]([N:64]4[CH:68]([CH3:69])[C:67](=[O:70])[N:66](CC5C=CC(OC)=CC=5)[C:65]4=[O:80])=[C:60]([F:81])[CH:59]=3)=[O:57])[CH2:52][CH2:51]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1>>[CH3:42][C:43]1[C:44]([N:50]2[CH2:51][CH2:52][N:53]([C:56]([C:58]3[CH:63]=[CH:62][C:61]([N:64]4[CH:68]([CH3:69])[C:67](=[O:70])[NH:66][C:65]4=[O:80])=[C:60]([F:81])[CH:59]=3)=[O:57])[CH2:54][CH2:55]2)=[N:45][CH:46]=[C:47]([CH3:49])[CH:48]=1
Reactant: COc1ccc(CN2C(=O)C(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3F)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)c(F)c3)CC2)c(C)c1

Procedure:
Using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (314 mg) described in Preparation Example 125 and 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (225 mg) described in Preparation Example 51 and by the reaction and treatment in the same manner as in Example 508, the title compound (141 mg) was obtained via 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-2-fluorophenyl}-3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(C1C=CC=CC=1S(O)(=O)=O)CCCCCCCCCCC.[N:33]([O-])=O.[Na+].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH:43]1[C:38]([NH2:37])=[CH:39][CH:40]=[C:41]([N:33]=[N:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:42]=1
Reactant: O=N[O-]
Reactant: Nc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Agent: [Na+]
Product: Nc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
13.8 grams of p-nitroaniline from Aldrich were added to 70 grams of alpha-methylnaphthylene from Crowley Chemical Company, New York, N.Y. and 49 grams of dodecylbenzene sulfonic acid from Pilot and the mixture was stirred at 45° C. until all ingredients had dissolved. Seven grams of NaNO2 from Pfaltz and Bauer were then added and the mix allowed to stir for twenty minutes and heated to 55° C. at which time 9.3 grams of aniline from Kessler Chemical of Pipersville, Pa. was added. The mixture immediately turned bright orange but was allowed to stir for six hours at about 65° C. The resulting material produced a bright orange dyeing on polyester similar in shade to Disperse Orange 3 purchased from Aldrich Chemical.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:9]/[C:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:5]=[CH:4][CH:3]=1.[BH3-]C#N.[Na+].CC(O)=O.CO>O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:10]2[C:15]([CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)c1cccc(C(CC)CC)c1/N=C/c1cccc(Br)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCC(CC)c1cccc(C(CC)CC)c1NCc1cccc(Br)n1

Procedure:
In argon atmosphere, a mixture of 11.2 g (28 mmol) of N-[(1E)-(6-bromopyridin-2-yl)methylene]-2,6-bis(1-ethylpropyl)aniline, 2.80 g (45 mmol) of NaBH3CN, 1 ml of AcOH and 230 ml of methanol was refluxed for 12 h. The obtained mixture was cooled, poured into 300 ml of water, and then crude product was extracted with 3×200 ml of ethyl acetate. The combined extract was dried over Na2SO4 and evaporated to dryness. Yield 10.3 g (93%) of yellow oil. Anal. calc. for C23H31BrN2: C, 65.50; H, 7.75; N, 6.94. Found: C, 65.36; H, 7.69; N, 6.82. 1H NMR (CDCl3): δ 7.52 (m, 1H, 4-H in Py), 7.41 (m, 1H, 3-H in Py), 7.38 (m, 1H, 5-H in Py), 7.03-7.08 (m, 1H, 4-H in dipentylphenyl), 6.97-6.99 (m, 2H, 3, 5-H in dipentylphenyl), 4.10 (s, 2H, CH2NH), 3.73 (br.s, 1H, NH), 2.86 (m, 2H, CHEt2), 1.70 (m, 4H, CH2Me), 1.49 (m, 4H, CH2Me), 0.79 (t, J=7.3 Hz, 12H, CH2Me).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[NH2:11][CH2:12][CH2:13][OH:14].C(N(C(C)C)CC)(C)C>CC(O)C>[NH2:1][C:2]1[C:7]([NH:11][CH2:12][CH2:13][OH:14])=[N:6][C:5]([CH3:9])=[N:4][C:3]=1[Cl:10]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: NCCO
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(N)c(NCCO)n1
Temperature: 150 °C
Reaction time: 27 h
Yield: 61.5 %

Procedure:
Charge a 1 L auto-clave with 5-amino-4,6-dichloro-2-methylpyrimidine (50.0 g, 0.281 mol), 2-amino ethanol (18.8 g, 0.309 mol), diisopropylethylamine (54.5 g, 0.421 mol), and IPA (500 mL). Heat the mixture to 145-155° C., with stirring for 24 to 30 h. Cool the reaction to 25-30° C. Concentrate the reaction mixture, removing the solvent under vacuum below 50° C. Charge DCM (500 mL) into the mixture and stir at 10-25° C. for 2 h. Filter the mixture and dry the cake in the oven at 45-50° C. to give the product as a pale yellow solid (35.0 g). 1H NMR (dmso-d6): δ 6.76 (s, 1H); 4.79 (s, 3H); 3.53-3.37 (m, 4H); 2.09 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH2:22][CH2:21][C:15]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].FC(F)(F)C(C1C=CC(N2CCC3(CCN(S(C4C=CC=CC=4C(F)(F)F)(=O)=O)CC3)C2=O)=CC=1)O.[F:61][C:62]([F:74])([F:73])[C:63]([C:66]1[CH:71]=[CH:70][C:69](I)=[CH:68][CH:67]=1)([OH:65])[CH3:64]>>[F:61][C:62]([F:73])([F:74])[C:63]([C:66]1[CH:67]=[CH:68][C:69]([N:18]2[CH2:17][CH2:16][C:15]3([CH2:21][CH2:22][N:12]([S:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:23])[F:24])(=[O:11])=[O:10])[CH2:13][CH2:14]3)[C:19]2=[O:20])=[CH:70][CH:71]=1)([OH:65])[CH3:64]
Reactant: CC(O)(c1ccc(I)cc1)C(F)(F)F
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2
Agent: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2
Product: CC(O)(c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4C(F)(F)F)CC3)C2=O)cc1)C(F)(F)F

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(2-trifluoromethyl-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one, product of example 166 A) and 1,1,1-trifluoro-2-(4-iodo-phenyl)-propan-2-ol). White crystalline solid. MS (ESI): 551.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:7]([CH:14]=[CH2:15])[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:23](=[O:30])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[NH2:24]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:24][C:23](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:3][CH:4]=3)[O:9][C:8]([CH3:13])([CH3:12])[C:7]=2[CH:14]=[CH2:15])=[CH:17][CH:18]=1
Reactant: C=CC1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C
Reactant: CC(C)(C)OC(N)=O
Product: C=CC1=C(c2ccc(F)cc2)c2ccc(NC(=O)OC(C)(C)C)cc2OC1(C)C

Procedure:
The compound obtained in (1) described above (155 mg) and tert-butyl carbamate (280 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (185 mg) as a yellow powder.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].Cl>CC(O)C>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ncnc2cccnc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(Nc2ncnc3cccnc23)c1
Yield: 87 %

Procedure:
Reaction of 4-chloropyrido[3,2-d]pyrimidine (prepared as described in a previous experimental) with 3-bromoaniline in propan-2-ol containing a trace of conc. HCl at 50° C. for 30 min, followed by chromatography of the product on silica gel, gives 4-(3-bromophenyl)aminopyrido[3,2-d]pyrimidine (87% yield). 1H NMR (CDCl3) δ 9.19 (1H, brs), 8.83 (1H, s), 8.80 (1H, dd, J=4.3, 1.5 Hz), 8.29 (1H, brs), 8.19 (1H, dd, J=8.5, 1.5 Hz), 7.83 (1H, m), 7.76 (1H, dd, J=8.5, 4.3 Hz), 7.29-7.27 (2H, m)
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][C:20]=3[OH:32])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:33]1([CH2:39]N2CCCCC2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[OH-].[Na+].C(O)(=O)C>C1(C)C=C(C)C=C(C)C=1.C1(C)C=CC=CC=1>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:19]3[CH:24]=[C:23]([CH2:39][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][C:20]=3[OH:32])[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCN(CN2CCCCC2)CC1
Reactant: CCCCCCOc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCOc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1CN1CCCCC1
Temperature: 160 °C
Yield: 29.9 %

Procedure:
2,4-Diphenyl-6-(2-hydroxy-4-hexyloxyphenyl)-s-triazine (42.5 g, 0.1 mol), dipiperidinomethane (17.5 g, 0.096 mol) and sodium hydroxide (0.8 g, 0.02 mol) are dissolved in 42 g of mesitylene. The mixture is heated with agitation at 160° C. for 18 hours. Acetic acid (8.5 g) is then added and the reaction mixture is heated for 30 minutes at 120°-130° C. Toluene (300 ml) is added and the heating is continued till the reaction product dissolves. The reaction mixture is then cooled to room temperature and the product crystallizes to give 21 g of reaction product. The crude product is recrystallized from 500 ml of toluene to yield 15 g of final product.